Schizophrenia remains a sizable socioeconomic burden that continues to be treated with therapeutics based on 70-year old science. All currently approved therapeutics primarily target the dopamine D2 receptor to achieve their efficacy. Whilst dopaminergic dysregulation is a key feature in this disorder, the targeting of dopaminergic machinery has yielded limited efficacy and an appreciable side effect burden. Over the recent decades, numerous drugs that engage non-dopaminergic GPCRs have yielded a promise of efficacy without the deleterious side effect profile, yet none have successfully completed clinical studies and progressed to the market. More recently, there has been increased attention around non-dopaminergic GPCR-targeting drugs, notably KarXT, which demonstrated efficacy in some schizophrenia symptom domains. This provides renewed hope that effective schizophrenia may lay outside of the dopaminergic space. Despite the potential for muscarinic receptor- (and other well-characterised GPCR families) targeting drugs to treat schizophrenia, they are often plagued with complications such as lack of receptor subtype selectivity and peripheral on-target side-effects. Orphan GPCR studies have opened a new avenue of exploration with many demonstrating schizophrenia-relevant mechanisms and a favourable expression profile, thus offering potential for novel drug development. This review discusses centrally-expressed orphan G protein-coupled receptors: GPR3, GPR6, GPR12, GPR52, GPR85, GPR88 and GPR139 and their relationship to schizophrenia. We review their expression, signalling mechanisms and cellular function, in conjunction with small molecule development and structural insights. We seek to provide a snapshot of the growing evidence and development potential of new classes of schizophrenia therapeutics.

Benzoic acid is one of the most commonly used food preservatives, but currently exclusively produced in petrochemical processes. In this study, we describe a bio-based production pathway using an engineered strain of Pseudomonas taiwanensis. In a phenylalanine-overproducing strain, we heterologously expressed bacterial, yeast, and plant genes to achieve production of benzoate via a β-oxidation pathway. Strategic disruption of the native Pseudomonas benzoate degradation pathway further allowed the production of catechol and cis,cis-muconate. Taken together, this work demonstrates new routes for the microbial production of these industrially relevant chemicals from renewable resources.

Solving the world’s health challenges requires multidisciplinary collaborations that bring together the talents, experiences, resources, and ideas from multiple sectors in low and middle-income countries (LMIC) and high -income countries (HIC). Cystic Fibrosis (CF) was thought to be a disease of Caucasian populations from European decent. However, it has been shown to affect people from all ethnic backgrounds. CF care varies significantly for people with CF (pw CF) from HIC with median survival approaching 50 years of age, to LMIC with pw CF dying in infancy or early childhood. To address the discrepancy in quality of care and outcomes, we report on a collaboration between our team at the University of Michigan cystic fibrosis center (UoM CFC), through support from the Middle East CF Association (MECFA) and the CF Foundation (CFF), and a CF center in Turkey (Marmara University CF Center, Istanbul) to address deficiencies and improve quality of care in that center. The collaboration has been successful in improving Ma CFC data and patient care. This partnership can be viewed as a model of collaboration to be duplicated in other Middle East Countries and LMIC to deliver optimal CF care.

In a paper manufacturing system, it can be substantially important to detect machine failure before it occurs and take necessary maintenance actions to prevent a detrimental breakdown of the system. Multiple sensor data collected from a machine provides useful information on the system's health condition. However, it is hard to predict the system condition ahead of time due to the lack of clear ominous signs for future failures, a rare occurrence of failure events, and a wide range of sensor signals which might be correlated with each other. In this paper, we present two versions of feature extraction techniques based on the nearest neighbor combined with machine learning algorithms to detect a failure of the paper manufacturing machinery earlier than its occurrence from the multi-stream system monitoring data. First, for each sensor stream, the time series data is transformed into the binary form by extracting the class label of the nearest neighbor. We feed these transformed features into the decision tree classifier for the failure classification. Second, expanding the idea, the relative distance to the local nearest neighbor has been measured, results in the real-valued feature, and the support vector machine is used as a classifier. Our proposed algorithms are applied to the dataset provided by IISE 2019 data competition, and the results show the better performance than the given baseline.

Abstract Background: Subcutaneous implantable cardioverter defibrillators (S-ICDs) avoid complications secondary to transvenous leads, but inappropriate shocks (ISs) are frequent. Furthermore, IS data from patients with Brugada syndrome (BrS) with an S-ICD are scarce. Objective: We aimed to establish the incidence, mechanisms, and predictors of S-ICD in this population. Methods: We analyzed the clinical and electrocardiographic characteristics, automated screening test data, device programming, and IS occurrence in adult patients with BrS with an S-ICD. Results: Thirty-nine patients were enrolled (69% male, mean age at diagnosis 46±13 years, mean age at implantation 48±13 years). During a mean follow-up of 26±21 months, 18% patients experienced IS. Patients with IS were younger at the time of diagnosis (36±8 versus 48±13 years, p=0.018) and S-ICD implantation (38±9 versus 50±23 years, p=0.019) and presented with spontaneous type 1 Brugada ECG pattern more frequently at diagnosis or during follow-up (71% versus 25%, p=0.018). During automated screening tests, patients with IS showed lower QRS voltage in the primary vector in the supine position (0.58±0.26 versus 1.10±0.35 mV, p=0.011) and lower defibrillator automated screening score (DASS) in the primary vector in the supine (123±165 versus 554±390 mV, p=0.005) and standing (162±179 versus 486±388 mV, p=0.038) positions. Age at diagnosis was the only independent predictor of IS (hazard ratio=0.873, 95% confidence interval: 0.767-0.992, p=0.037). Conclusion: IS was a frequent complication in patients with BrS with an S-ICD. Younger age was independently associated with IS. A more thorough screening process might help prevent IS in this population.

Functional interaction between cancer cells and the surrounding microenvironment is still not sufficiently understood, which motivates the tremendous interest for the development of numerous in vitro and in vivo tumor models. Diverse parameters, e.g., transport of nutrients and metabolites, availability of space in the confinement, interaction with scaffolds, etc. make an impact on the size, shape, and metabolism of the tumoroids. Herein, we demonstrate the fluidics-based low-cost methodology to reproducibly generate the alginate and alginate-chitosan microcapsules and apply it to grow human hepatoma (HepG2) tumoroids of different dimensions and geometries. Focusing specifically on the composition and thickness of the hydrogel shell, permeability of the microcapsules is selectively tuned. The diffusion of the selected benchmark molecules through the shell has been systematically investigated using both, experiments and simulations, which is essential to ensure efficient mass transfer of small molecules and prevent large substances from reaching the encapsulated cells. Depending on available space, phenotypically different 3D cell assemblies have been observed inside the capsules, varying in the tightness of cell aggregations and their shapes. Metabolic activity of tumoroids in microcapsules was confirmed by tracking the turnover of testosterone to androstenedione with chromatography studies in a metabolic assay. Because of the high reproducibility, compartmentalization, and facile tuning of the shell thickness and permeability, our system is not only a great platform for the formation of cancer tumoroids, but also a promising tool for the design and engineering of other cells.

Abstract: Background: The 2019 coronavirus disease (COVID-19) pandemic is a public health emergency and constitutes a challenge to psychological health. This study aimed to assess the psychological conditions among university students in Saudi Arabia during the COVID-19 pandemic. Material and Methods: During the period between the 4th and 18th of June 2020, the students at Umm AlQura University in Saudi Arabia were invited to complete an online survey. The survey assessed their sociodemographic characteristics, educational disciplines, and manifestations of depression, anxiety, and stress as determined by the Depression Anxiety Stress Scale-21 (DASS-21). Results: The study included 936 students. Of them, 41.1% had depressive symptoms (31.7% mild to moderate and 9.4% severe to very severe), 26.9% had anxiety symptoms (15.8% mild to moderate and 11.1% severe to very severe), and 22.4% had stress symptoms (15.2% mild to moderate and 7.2% severe to very severe). Students who reported having a friend or relative infected with or died from COVID-19, watching or reading news about the pandemic ≥2 hours/day, and not having emotional support from family, university, and society were more likely to show psychological problems. Conclusion: Symptoms of depression, anxiety, and stress were common among Saudi university students. Psychological counseling and support should be provided to university students in Saudi Arabia. Keywords: Depression; Anxiety; Stress; COVID-19; University students; Saudi Arabia

Objective: To evaluate whether prolonged operative time is negatively associated with post-operative complications and length of stay in patients undergoing microvascular free flap reconstruction for complex head and neck defects. Methods: 342 consecutive patients undergoing microvascular reconstruction for head and neck defects between 2017-2019 at a single institution were evaluated. Operative outcomes and operative time were compared whilst controlling for patient and treatment related factors. Results: Mean operative time was 551 minutes and length of stay was 16.2 days. An 11% increase in the risk of a post-operative complication was observed for every additional hour of operative time (OR 1.11, 95%CI 1.03 – 1.21, p=0.011) after adjusting for patient and treatment factors. A cut-off of 9 hours yielded a 92% increase in complications on either side of this (OR 1.92, 95%CI 1.18 – 3.13, p=0.009). Increased operative time was also associated with increased length of stay and return to theatres, but not medical complications. Conclusion: Prolonged operative time is significantly associated with increase surgical complications, length of stay and return to theatres when performing microvascular reconstructive surgery for head and neck defects. Keywords : free flap, microsurgery, operative time, length of hospital stay, complication rate, head and neck surgery Key points : 1. This study analyzed a contemporary cohort over a relatively short period where outcomes can reliably be recorded and verified 2. This is the first Australian study that demonstrated operative time as it relates to surgical technique, comparing pedicled and free flaps and also stratified by flap type, oncological resection, or comorbidity 3. Operations more than 9 hours duration were associated with an 89% increase in the odds of developing a surgical complication 4. Prolonged operative time was also significantly associated with length of stay and return to theatres 5. Future studies are needed to investigate associations with each component of operative time element separately in a multi institutional design

Poultry and poultry-derived products such as meat and eggs are among the main sources of non-typhoidal Salmonella (NTS) transmission to the human. Therefore, we performed a systematic review and used random-effects meta-analyses to 1) estimate the prevalence of NTS in poultry samples from birds, products and subproducts, and environmental samples, 2) examine the diversity and frequency of their serovars, and 3) estimate the prevalence and profiles of antimicrobial resistance (AMR) in NTS isolates reported in studies from the Americas. We included 157 studies from 15 countries comprising 261,408 poultry samples and estimated an overall pooled prevalence of 17.9% (95% CI: 10.8–26.3) in birds, 21.8% (17.7–26.1) in products and subproducts, and 29.5% (24.2–35.1) in environmental samples. At the national level, the prevalence of NTS was heterogenous across countries with the highest values in Mexico, the USA, and Canada. In total, 131 serovars were identified from 13,388 isolates, Heidelberg, Kentucky, Enteritidis, and Typhimurium were the most prevalent in the overall top 10 ranking (range 6.5–20.8%). At the national level, Enteritidis and Typhimurium were identified in most of the countries, though with national differences in their ranks. The prevalence of AMR increased from 24.1% for 1 antibiotic, to 36.2% for 2-3 antibiotics, and 49.6% for ≥ 4 antibiotics. Kentucky, Heidelberg, Typhimurium, and Enteritidis were the serovars with the highest prevalence of AMR and tetracycline, ampicillin, streptomycin, ceftiofur, and amoxicillin-clavulanic acid were the top five antibiotics to which NTS isolates were resistant. In conclusion, NTS was distributed through the avian production chain with high and heterogenous values of prevalence in poultry samples. Besides, there were distinctive patterns of serovars distribution across countries and an alarming prevalence of AMR among zoonotic serovars.

Background: Internationally, the COVID-19 pandemic severely curtailed access to hospital facilities for those awaiting elective/semi elective procedures. For allergic children in Ireland, already waiting up to 4yr for an elective oral food challenge (OFC), the restrictions signified indefinite delay. At the time of the initiative there were approx 900 children on the Chidren’s Health Ireland(CHI) waiting list. In July 2020, a project was facilitated by short term(6wk) access to an empty COVID stepdown facility built, in a hotel conference centre, commandeered by the Health Service Executive Ireland(HSE). The aim was to the achieve rapid rollout of an off-site OFC service, delivering high throughput of long waiting patients, while aligning with hospital existing policies and quality standards, international allergy guidelines and national social distancing standards. Methods: The working group engaged key stakeholders to rapidly develop an offsite OFC facility. Consultant Paediatric Allergists, Consultant Paediatricians, trainees and Allergy Clinical Nurse Specialists were seconded from other duties. The facility was already equipped with hospital beds, bedside monitors(BP, Pulse, Oxygen saturation) bedside oxygen. All medication and supplies had to be brought from the base hospital. Daily onsite consultant anaesthetic cover was resourced and a resuscitation room equipped. Standardised food challenge protocols were created. Access to onsite hotel chef facilitated food preparation. A risk register was established. Results: After 6wks planning, the remote centre became operational on 7/9/20, with the capacity of 27 OFC/day. 474 challenges were commenced, 465 (98%) were completed, 9(2%) were inconclusive. 135(29.03%) OFC were positive, 25(5%) causing anaphylaxis. No child required advanced airway intervention. 8 children were transferred to the base hospital. The CHI allergy waiting list was reduced by almost 60% in only 24 days. Conclusions: OFCs remain a vital tool in the care of allergic children, with their cost saving and quality of life benefits negatively affected by delay in their delivery. This project has shown it is possible to have huge impacts on a waiting list efficiently, effectively and safely with good planning and staff buy in – even in a pandemic. Adoption of new, flexible and efficient models of service delivery will be important for healthcare delivery in the post-COVID-19 era.

Known elicitors of plant defenses against eggs of herbivorous insects are low-molecular-weight organic compounds associated with the eggs. However, previous studies provided evidence that also proteinaceous compounds present in secretion associated with eggs of the herbivorous sawfly Diprion pini can elicit defensive responses in Pinus sylvestris. Pine responses induced by the proteinaceous secretion are known to result in enhanced emission of (E)-β-farnesene, which attracts egg parasitoids killing the eggs. Here, we aimed to identify the defense-eliciting protein and elucidate its function. After isolating the defense-eliciting protein from D. pini egg secretion by ultrafiltration and gel electrophoresis, we identified it by MALDI-ToF mass spectrometry as an annexin-like protein, which we named “diprionin”. Further GC-MS analyses showed that pine needles treated with heterologously expressed diprionin released enhanced quantities of (E)-β-farnesene. Our bioassays confirmed attractiveness of diprionin-treated pine to egg parasitoids. Expression of several pine candidate genes involved in terpene biosynthesis and regulation of ROS homeostasis was similarly affected by diprionin and natural sawfly egg deposition. However, the two treatments had different effects on expression of pathogenesis related genes (PR1, PR5). Diprionin is the first egg-associated proteinaceous elicitor of indirect plant defense against insect eggs described so far.

Background During automated radiofrequency (RF) annotation-guided pulmonary vein isolation (PVI), respiratory motion adjustment (RMA) is recommended, yet lacks in vivo validation. Methods Following contact force (CF) PVI (continuous RF, 30W) using general anaesthesia and automated RF annotation-guidance (VISITAG™: force-over-time 100% minimum 1g; 2mm position stability; ACCURESP™ RMA “off”) in 25 patients, we retrospectively examined RMA settings “on” versus “off” at the left atrial posterior wall (LAPW). Results Respiratory motion detection occurred in 8, permitting offline retrospective comparison of RMA settings. Significant differences in LAPW RF auto-annotation occurred according to RMA setting, with curves displaying catheter position, CF and impedance data indicating “best-fit” for catheter motion detection using RMA “off”. Comparing RMA “on” versus “off”, respectively: Total annotated sites 82 versus 98; median RF duration per-site 13.3s versus 10.6s (p<0.0001); median force time integral 177g.s versus 130g.s (p=0.0002); mean inter-tag distance (ITD) 6.0mm versus 4.8mm (p=0.002). Considering LAPW annotated site 1-to-2 transitions resulting from deliberate catheter movement, 3 concurrent with inadvertent 0g CF demonstrated <0.6s difference in RF duration. However, 13 deliberate catheter movements during constant tissue contact (ITD range 2.1 – 7.0mm) demonstrated (mean) site-1 RF duration difference 3.7s (range: -1.3 to 11.3s): considering multiple measures of catheter position instability, the appropriate indication of deliberate catheter motion occurred with RMA “off” in all. Conclusions ACCURESP™ respiratory motion adjustment importantly delayed the identification of deliberate and clinically relevant catheter motion during LAPW RF delivery, rendering auto-annotated RF display invalid. Operators seeking greater accuracy during auto-annotated RF delivery should avoid RMA use.

The construction of morphological character matrices is central to paleontological systematic study, which extracts paleontological information from fossils. Although the word information has been repeatedly mentioned in a wide array of paleontological systematic studies, its meaning has rarely been clarified and there has not been a standard to measure paleontological information due to the incompleteness of fossils, difficulty of recognizing homologous and homoplastic structures, etc. Here, based on information theory, we show the deep connections between paleontological systematic study and communication system engineering. It is information, the decrease of uncertainty, in morphological characters that distinguishes operational taxonomic units (OTUs) and reconstructs evolutionary history. We propose that concepts in communication system engineering such as source coding and channel coding correspond in paleontological studies to the construction of diagnostic features and the entire character matrices, which should be distinguished as how typical communication systems are engineered because these two steps serve dual purposes. With character matrices from six different vertebrate groups, we analyzed their information properties including source entropy, mutual information, and channel capacity. Estimation of channel capacity shows upper limits of all matrices in transmitting paleontological information, indicating that, due to the presence of noise, too many characters not only increase the burden in character scoring, but also may decrease quality of matrices. Information entropy, which measure how informative a variable is, of each character is tested as a weighting criterion in parsimony-based systematic studies, the results show high consistence with existing knowledge with both good resolution and interpretability.

A novel fermentation process was developed in which renewable electricity is indirectly used as a fermentation substrate, synergistically decreasing both the consumption of sugar as a first generation carbon source and emission of the greenhouse gas CO2. To achieve this, a glucose-based process is co-fed with formic acid, which can be generated by capturing CO2 from fermentation offgas followed by electrochemical reduction with renewable electricity. This ‘closed carbon loop’ concept is demonstrated by a case study in which co-feeding formic acid is shown to significantly increase the yield of biomass on glucose of the industrially relevant yeast species Yarrowia lipolytica. First, the optimal feed ratio of formic acid to glucose is established using chemostat cultivations. Subsequently, guided by a dynamic fermentation process model, a fed-batch protocol is developed and demonstrated on laboratory scale. Finally, the developed fed-batch process is proven to be scalable to pilot scale. An extension of this proven concept to also recycle the O2 that is co-generated with the formic acid to the fermentation process for intensification purposes, and a potential further application of the concept to anaerobic fermentations are discussed.

In this investigation, CO2 capture performance of zeolite 13X monoliths with 600 and 800 cpsi in presence of SO2/NO impurities under dry and humid conditions were evaluated and compared with that of 13X beads. Dynamic breakthrough tests demonstrated a drastic reduction in CO2 capture capacity and deterioration of kinetics under dry-clean conditions, whereas, upon switching the feed from a clean gas to contaminated gas which contained SO2 and NO, different adsorption performance was observed. Specifically, in dry-contaminated mode, the adsorbents retained their capture capacities with comparable kinetics to that of dry-clean feed conditions, however, in humid-contaminated mode, the adsorbents experienced improved CO2 uptake and CO2/N2 selectivity, albeit at the expense of deteriorated kinetics. These findings indicate that the presence of SO2 and NO contaminants, especially SO2 contaminants, lead to dramatic changes in the adsorption performance of zeolite 13X monoliths, indicating the importance of evaluating adsorbent materials under realistic conditions.

Online Social Networks (OSNs) have grown exponentially in the last few years due to their applications in real life like marketing, recommendation systems, and social awareness campaigns. One of the most important research areas in this field is Influence Maximization (IM). IM pertains to finding methods to maximize the spread of information (or influence) across a social network. Previous works in IM have focused on using a pre-defined edge propagation probability or using the Hurst exponent (H) to identify which nodes to be activated. This is calculated on the basis of self-similarity in the time series depicting a user’s (node) past temporal interaction behaviour. In this work, we propose a Time Series Characteristic based Hurst-based Diffusion Model (TSC-HDM). The model calculates Hurst Exponent (H) based on the stationary or non-stationary characteristic of the time series. Furthermore, our model selects a handful of seed nodes and activates every seed node’s inactive successor only if H>0.5 . The process is continued until the activation of successor nodes is not possible. The proposed model was tested on 4 datasets - UC Irvine messages, Email EU-Core, Math Overflow 3, and Linux Kernel mailing list. We have also compared the results against 4 other Influence Maximisation models - Independent Cascade (IC), Weighted Cascade (WC), Trivalency (TV), and Hurst-based Influence Maximisation (HBIM). Our model achieves as much as 590% higher expected influence spread as compared to the other models. Moreover, our model attained 344% better average influence spread than other state-of-the-art models.

Our purpose is to assess epidemiological agent-based models– or ABMs - of the SARS-CoV-2 pandemic methodologically. The rapid spread of the outbreak requires fast-paced decision-making regarding mitigation measures. However, the evidence for the efficacy of non-pharmaceutical interventions such as imposed social distancing and school or workplace closures is scarce: few observational studies use quasi-experimental research designs, and conducting randomized controlled trials seems infeasible. Additionally, evidence from the previous coronavirus outbreaks of SARS and MERS lacks external validity, given the significant differences in contagiousness of those pathogens relative to SARS-CoV-2. To address the pressing policy questions that have emerged as a result of COVID-19, epidemiologists have produced numerous models that range from simple compartmental models to highly advanced agent-based models. These models have been criticized for involving simplifications and lacking empirical support for their assumptions. In order to address these voices and methodologically appraise epidemiological ABMs, we consider AceMod (the model of the COVID-19 epidemic in Australia) as an example of the modeling practice. Our case study shows that, although epidemiological ABMs involve simplifications of various sorts, the key characteristics of social interactions and the spread of SARS-CoV-2 are represented sufficiently accurately. This is the case because these modelers treat empirical results as inputs for constructing modeling assumptions and rules that the agents follow; and they use calibration to assert the adequacy to benchmark variables. Given this, we claim that the best epidemiological ABMs are models of actual mechanisms and deliver both mechanistic and difference-making evidence. Furthermore, the efficacy claims are not only internally valid but also adequately describe the effects of interventions in the targets of the models. We also discuss the limitations of ABMs and put forward policy recommendations.

We describe six teenagers presenting with fever and severe abdominal symptoms admitted with concerns for multisystem inflammatory syndrome in children (MIS-C). Laboratory evaluation revealed elevated markers of inflammation, lymphopenia, and increased d-dimers. Imaging studies revealed multifocal airspace disease and ground-glass opacities. SARS-CoV-2 PCR and serologies were negative. All patients reported a history of vaping, prompting E-cigarette, or vaping, product use-associated lung injury (EVALI) diagnosis. MIS-C has overlapping clinical and laboratory features highlighting the added challenge of diagnosing EVALI during the COVID-19 pandemic.