Proteogenomic Gene Structure Validation in the Pineapple Genome.

MD2 pineapple (Ananas comosus) is the second most important tropical crop that preserves crassulacean acid metabolism (CAM), which has high water-use efficiency and is fast becoming the most consumed fresh fruit worldwide. Despite the significance of environmental efficiency and popularity, until very recently, its genome sequence has not been determined and a high-quality annotated proteome has not been available. Here, we have undertaken a pilot proteogenomic study, analyzing the proteome of MD2 pineapple leaves using liquid chromatography-mass spectrometry (LC-MS/MS), which validates 1781 predicted proteins in the annotated F153 (V3) genome. In addition, a further 603 peptide identifications are found that map exclusively to an independent MD2 transcriptome-derived database but are not found in the standard F153 (V3) annotated proteome. Peptide identifications derived from these MD2 transcripts are also cross-referenced to a more recent and complete MD2 genome annotation, resulting in 402 nonoverlapping peptides, which in turn support 30 high-quality gene candidates novel to both pineapple genomes. Many of the validated F153 (V3) genes are also supported by an independent proteomics data set collected for an ornamental pineapple variety. The contigs and peptides have been mapped to the current F153 genome build and are available as bed files to display a custom gene track on the Ensembl Plants region viewer. These analyses add to the knowledge of experimentally validated pineapple genes and demonstrate the utility of transcript-derived proteomics to discover both novel genes and genetic structure in a plant genome, adding value to its annotation.

Non-Insulin-Based Drug Entities Used to Treat Diabetes Type 2 Disease (T2DM), Based on Natural Products from All Sources.

Diabetes type 2 (T2DM) is the non-insulin-linked disease that is now becoming a major problem not only in the West but also in Asia (particularly in China and close geographic areas). Unlike the childhood onset diabetic disease (T1DM), which is effectively due to lack of insulin production and is maintained by insulin injection, T2DM is best thought of as an adult disease often being caused by what is now considered "metabolic syndrome" or the culmination of too many insults to the body, in particular obesity and its "coupled diseases" including heart problems. Its symptoms were described in ancient times not only in Europe but also in Asia and with later (1600s) anecdotal reports from South America. In all cases, the diagnostic was "sweet urine" due to the excretion of large amounts of glucose in the urine. This review covers the non-insulin agents approved from 1990 to 2021 from a historical aspect and discussions of the latest agents and can be considered an extension of the author's previous drug source reviews, but this time concentrating on nominally one disease entity, though metabolic syndrome is a collection of ailments.

Caged Xanthones and Biphenyls Isolated from the Tropical Plant Garcinia lateriflora.

Four cytotoxic heptacyclic caged-xanthones [gambogefic acids B-E (1-4)], a cytotoxic hexacyclic caged-xanthone [garcilatelic acid (5)], and four biphenyl derivatives [garcilatelibiphenyls A-D (6-9)] were newly isolated in a phytochemical study of a 50% MeOH/CH2Cl2 extract of Garcinia lateriflora (Clusiaceae). The isolated compounds were evaluated for antiproliferative activity against five human tumor cell lines including a vincristine-resistant line. The new caged-xanthones displayed potent activity with IC50 values from 0.5 to 6.7 µM against all tested tumor cell lines.

Unusual Vilasinin-Class Limonoids from Trichilia rubescens.

Eight vilasinin-class limonoids, including the unusually chlorinated rubescins K-M (1-3), the 2,3-epoxylated rubescin N (4), and rubescins O-R (5-8), were newly isolated from Trichilia rubescens. The structures of the isolated compounds were determined through spectroscopic and spectrometric analyses, as well as ECD calculations. The natural occurrence of chlorinated limonoids 1-3 was confirmed by chemical methods and HPLC analysis of a roughly fractionated portion of the plant extract. Eight selected limonoids, including previously known and new compounds, were evaluated for antiproliferative activity against five human tumor cell lines. All tested limonoids, except 8, exhibited significant potency, with IC50 values of <10 µM; in particular, limonoid 14 strongly inhibited tumor cell growth, with IC50 values of 0.54-2.06 µM against all tumor cell lines, including multi-drug-resistant cells.

AlacatDesigner─Computational Design of Peptide Concatamers for Protein Quantitation.

Protein quantitation via mass spectrometry relies on peptide proxies for the parent protein from which abundances are estimated. Owing to the variability in signal from individual peptides, accurate absolute quantitation usually relies on the addition of an external standard. Typically, this involves stable isotope-labeled peptides, delivered singly or as a concatenated recombinant protein. Consequently, the selection of the most appropriate surrogate peptides and the attendant design in recombinant proteins termed QconCATs are challenges for proteome science. QconCATs can now be built in a "a-la-carte" assembly method using synthetic biology: ALACATs. To assist their design, we present "AlacatDesigner", a tool that supports the peptide selection for recombinant protein standards based on the user's target protein. The user-customizable tool considers existing databases, occurrence in the literature, potential post-translational modifications, predicted miscleavage, predicted divergence of the peptide and protein quantifications, and ionization potential within the mass spectrometer. We show that peptide selections are enriched for good proteotypic and quantotypic candidates compared to empirical data. The software is freely available to use either via a web interface AlacatDesigner, downloaded as a Desktop application or imported as a Python package for the command line interface or in scripts.

Examining Daily Associations Among Sleep, Stress, and Blood Pressure Across Adulthood.

BACKGROUND: Sleep can have consequential effects on people's health and well-being, and these effects may vary among younger and older adults. PURPOSE: The goal of the present study was to investigate how sleep relates to physiologic and stress responses in daily life across adulthood. METHODS: We used an Ecological Momentary Assessment method in a large sample of participants (N = 4,359; Mage = 46.75, SD = 12.39; 69.30% male, 29.85% female) who completed morning sleep diaries, reported subjective stress, and recorded their heart rate and blood pressure for 21 days. Sleep was assessed with self-reports of duration, efficiency, and quality. RESULTS: Using multilevel modeling, between-person analyses showed that sleep duration, efficiency, and quality were negatively related to morning heart rate and stress, such that people who slept longer, more efficiently, or better experienced lower heart rate and stress compared to those who slept shorter, less efficiently, or worse. Within-person analyses showed that sleep duration, efficiency, and quality predicted morning heart rate, blood pressure (though less consistently), and stress. That is, people experienced lower heart, blood pressure, and stress following nights when they slept longer, more efficiently, or better than they typically did. These within-person relationships were moderated by age, such that the effects of better and longer sleep on lower morning heart rate, blood pressure, and stress were stronger among younger than older adults. CONCLUSION: These findings suggest that daily variations in sleep show immediate associations with stress and physiologic responses, but these daily variations have a stronger relationship among younger compared to older adults.

We examined how sleep influences people's blood pressure and well-being among younger and older adults. Participants (N = 4,359) completed questionnaires in the morning over the course of 21 days and reported how well and how long they slept that night and how stressed they felt. They also recorded their heart rate and blood pressure using an optic sensor on their phones. Our analyses showed that people who slept longer, more efficiently, or better experienced lower levels of heart rate and stress on average compared to those who slept shorter, less efficiently, or worse. In addition, we examined how changes in sleep influenced stress, heart rate, and blood pressure for a given individual. These analyses showed that people experienced lower heart rate, lower blood pressure, and less stress following nights when they slept longer, more efficiently, or better than they typically did. These relationships varied by age such that the beneficial effects of sleep were more pronounced among younger than older adults. That is, receiving a particularly good night of sleep tends to be beneficial for younger adults, whereas older adults may not be influenced as strongly by the quality and duration of their sleep.

Study protocol for "In-vehicle sensors to detect changes in cognition of older drivers".

BACKGROUND: Driving is a complex behavior that may be affected by early changes in the cognition of older individuals. Early changes in driving behavior may include driving more slowly, making fewer and shorter trips, and errors related to inadequate anticipation of situations. Sensor systems installed in older drivers' vehicles may detect these changes and may generate early warnings of possible changes in cognition. METHOD: A naturalistic longitudinal design is employed to obtain continuous information on driving behavior that will be compared with the results of extensive cognitive testing conducted every 3 months for 3 years. A driver facing camera, forward facing camera, and telematics unit are installed in the vehicle and data downloaded every 3 months when the cognitive tests are administered. RESULTS: Data processing and analysis will proceed through a series of steps including data normalization, adding information on external factors (weather, traffic conditions), and identifying critical features (variables). Traditional prediction modeling results will be compared with Recurring Neural Network (RNN) approach to produce Driver Behavior Indices (DBIs), and algorithms to classify drivers within age, gender, ethnic group membership, and other potential group characteristics. CONCLUSION: It is well established that individuals with progressive dementias are eventually unable to drive safely, yet many remain unaware of their cognitive decrements. Current screening and evaluation services can test only a small number of individuals with cognitive concerns, missing many who need to know if they require treatment. Given the increasing number of sensors being installed in passenger vehicles and pick-up trucks and their increasing acceptability, reconfigured in-vehicle sensing systems could provide widespread, low-cost early warnings of cognitive decline to the large number of older drivers on the road in the U.S. The proposed testing and evaluation of a readily and rapidly available, unobtrusive in-vehicle sensing system could provide the first step toward future widespread, low-cost early warnings of cognitive change for this large number of older drivers in the U.S. and elsewhere.

Authenticity, meaning in life, and life satisfaction: A multicomponent investigation of relationships at the trait and state levels.

OBJECTIVE: The present study sought to examine: (1) how the components of authenticity (i.e., authentic living, self-alienation, accepting external influence) relate to one another at between- and within-person levels of analysis; (2) how the authenticity facets relate to meaning in life (i.e., purpose, comprehension, mattering) and life satisfaction at these levels of analysis; and (3) whether these relationships persist when controlling for affect and self-esteem. METHOD: Canadian undergraduates (N = 203) completed a trait questionnaire and end-of-day reports on these constructs for two weeks (n = 2335). RESULTS: At between- and within-person levels, authentic living was negatively associated with self-alienation and accepting external influence, while the latter two facets were positively associated. Authentic living was positively related to well-being and predicted greater well-being the following day. Alternatively, self-alienation and accepting external influence were negatively related to well-being, and self-alienation predicted lower well-being the following day. Relationships involving authentic living and self-alienation were more robust than those involving accepting external influence. CONCLUSION: Extending research on authenticity beyond between-person relationships, our findings show that daily states of authenticity predict well-being in nuanced ways, depending on the facet of authenticity. This highlights the importance of distinguishing levels of analyses and facets of authenticity.

Cannabinoids and synthetic cannabinoids as a cause of death: Trends and their healthcare implications.

INTRODUCTION: Cannabis remains one of the most widely used illicit substances globally, with 188 million users in 2017. In the United States, nearly 50 million people are reported to have used cannabis in 2020. More research is needed because of the dramatic increase in cannabis use and the perception that its use has minimal risk. DESIGN: The researchers used a retrospective design for this study. METHODS: We used the Florida Department of Law Enforcement data from 2014 to 2020 for this study. We used descriptive statistics to report the characteristics of decedents whose cause of death (COD) was associated with cannabinoid (CB) and synthetic cannabinoid (SC) use. We used a general linear model with repeated measures to examine CB and SC death rate trends. RESULTS: A total of 386 decedents' COD in Florida was associated with CB and SC use. Nearly 28% of decedents were 45-54 years, male (87.8%), and non-Hispanic whites (65.3%). One hundred percent of CB-related decedents died in urban counties. In rural counties, SC decedents accounted for 28.3% of deaths. Of decedents in rural counties, 39.9% were African American. Most decedents (with CB and SC use) died from accidents (98.7%), with 12.6% of cases involving cardiovascular-related illnesses. CONCLUSION: CBs and SCs as a COD pose a legitimate health problem to society. More people ages 45-54 died from CBs and SCs. Drug intoxications (from CBs and SCs) and motor vehicle collisions accounted for most of the accidents reported while under the influence of CBs and SCs. While most decedents from both CBs and SCs were non-Hispanic whites, a substantial proportion of African Americans died from SCs as a COD in rural counties. It is important that the public become aware of the risks for adverse effects of CB and SC. The public needs to be aware that CB and SC use can exacerbate cardiac-related conditions. CLINICAL RELEVANCE: This study has clinical relevance to patient safety. CB and SC use contributes to motor vehicle accidents and can cause adverse effects including death.

Biophysical insights into OR2T7: Investigation of a potential prognostic marker for glioblastoma.

Glioblastoma multiforme (GBM) is the most aggressive and prevalent form of brain cancer, with an expected survival of 12-15 months following diagnosis. GBM affects the glial cells of the central nervous system, which impairs regular brain function including memory, hearing, and vision. GBM has virtually no long-term survival even with treatment, requiring novel strategies to understand disease progression. Here, we identified a somatic mutation in OR2T7, a G-protein-coupled receptor (GPCR), that correlates with reduced progression-free survival for glioblastoma (log rank p-value = 0.05), suggesting a possible role in tumor progression. The mutation, D125V, occurred in 10% of 396 glioblastoma samples in The Cancer Genome Atlas, but not in any of the 2504 DNA sequences in the 1000 Genomes Project, suggesting that the mutation may have a deleterious functional effect. In addition, transcriptome analysis showed that the p38α mitogen-activated protein kinase (MAPK), c-Fos, c-Jun, and JunB proto-oncogenes, and putative tumor suppressors RhoB and caspase-14 were underexpressed in glioblastoma samples with the D125V mutation (false discovery rate < 0.05). Molecular modeling and molecular dynamics simulations have provided preliminary structural insight and indicate a dynamic helical movement network that is influenced by the membrane-embedded, cytofacial-facing residue 125, demonstrating a possible obstruction of G-protein binding on the cytofacial exposed region. We show that the mutation impacts the "open" GPCR conformation, potentially affecting Gα-subunit binding and associated downstream activity. Overall, our findings suggest that the Val125 mutation in OR2T7 could affect glioblastoma progression by downregulating GPCR-p38 MAPK tumor-suppression pathways and impacting the biophysical characteristics of the structure that facilitates Gα-subunit binding. This study provides the theoretical basis for further experimental investigation required to confirm that the D125V mutation in OR2T7 is not a passenger mutation. With validation, the aforementioned mutation could represent an important prognostic marker and a potential therapeutic target for glioblastoma.

Cheminformatic analysis of natural product-based drugs and chemical probes.

Covering: 1981 to 2019Natural products continue to play a major role in drug discovery, with half of new chemical entities based structurally on a natural product. Herein, we report a cheminformatic analysis of the structural and physicochemical properties of natural product-based drugs in comparison to top-selling brand-name synthetic drugs, and a selection of chemical probes recently discovered from diversity-oriented synthesis libraries. In this analysis, natural product-based drugs covered a broad range of chemical space based on size, polarity, and three-dimensional structure. Natural product-based structures were also more prevalent in top-selling drugs of 2018 compared to 2006. Further, the drugs clustered well according to biosynthetic origins, but less so based on therapeutic classes. Macrocycles occupied distinctive and relatively underpopulated regions of chemical space, while chemical probes largely overlapped with synthetic drugs. This analysis highlights the continued opportunities to leverage natural products and their pharmacophores in modern drug discovery.

Effectiveness of SPECT/CT Imaging for Sentinel Node Biopsy Staging of Primary Cutaneous Melanoma and Patient Outcomes.

PURPOSE: Coregistered SPECT/CT can improve accuracy of sentinel node biopsy (SNB) for staging melanoma. This benefit has implications for pathology services and surgical practice with increased diagnostic and surgical workload. The purpose of this study was to investigate the effectiveness of SPECT/CT imaging. METHODS: SNB data were collected over a 10-year period. Preoperative SLN mapping was performed by using planar lymphoscintigraphy (LSG) for all patients (n = 1522) and after October 2015, patients underwent a second co-registered SPECT/CT scan (n = 559). The patients were stratified according to the imaging protocol. The number of nodes and nodal basins were assessed. The reasons for cancellation also were assessed. RESULTS: A total of 95% (1446/1522) of patients underwent a successful SNB procedure. Significantly more sentinel nodes were identified by the SPECT/CT protocol (3 vs. 2; p < 0.0001). More patients were cancelled in the SPECT/CT cohort (9.3% vs. 2.5%; p < 0.0001). Head & neck, lower limb, and AJCC IB primaries were significantly less likely to proceed to SNB. SPECT/CT identified significantly more positive SNBs (20.9% vs. 16.5%; p = 0.038). SPECT/CT imaging was associated with improved disease-free (hazard ratio [HR] = 0.74; 95% confidence interval [CI]: 0.54-1.0); p = 0.048) and disease-specific survival (HR = 0.48; 95% CI: 0.3-0.78; p = 0.003). Patients who did not proceed to SNB had a significantly increased nodal relapse rate (23.5% vs. 6.8%; HR = 3.4; 95% CI: 1.9-6.2; p < 0.0001) compared with those who underwent SNB. CONCLUSIONS: This large cohort study confirms the increased accuracy of SPECT/CT for identifying SLN metastases, which would appear to have a significant therapeutic benefit, although an increased risk of cancellation of the SNB procedure on the day of surgery.

Future directions for the discovery of natural product-derived immunomodulating drugs: an IUPHAR positional review.

Drug discovery from natural sources is going through a renaissance, having spent many decades in the shadow of synthetic molecule drug discovery, despite the fact that natural product-derived compounds occupy a much greater chemical space than those created through synthetic chemistry methods. With this new era comes new possibilities, not least the novel targets that have emerged in recent times and the development of state-of-the-art technologies that can be applied to drug discovery from natural sources. Although progress has been made with some immunomodulating drugs, there remains a pressing need for new agents that can be used to treat the wide variety of conditions that arise from disruption, or over-activation, of the immune system; natural products may therefore be key in filling this gap. Recognising that, at present, there is no authoritative article that details the current state-of-the-art of the immunomodulatory activity of natural products, this in-depth review has arisen from a joint effort between the International Union of Basic and Clinical Pharmacology (IUPHAR) Natural Products and Immunopharmacology Sections, with contributions from a number of world-leading researchers in the field of natural product drug discovery, to provide a "position statement" on what natural products has to offer in the search for new immunomodulatory argents. To this end, we provide a historical look at previous discoveries of naturally occurring immunomodulators, present a picture of the current status of the field and provide insight into the future opportunities and challenges for the discovery of new drugs to treat immune-related diseases.

Extremophilic Fungi from Marine Environments: Underexplored Sources of Antitumor, Anti-Infective and Other Biologically Active Agents.

Marine environments are underexplored terrains containing fungi that produce a diversity of natural products given unique environmental pressures and nutrients. While bacteria are commonly the most studied microorganism for natural products in the marine world, marine fungi are also abundant but remain an untapped source of bioactive metabolites. Given that their terrestrial counterparts have been a source of many blockbuster antitumor agents and anti-infectives, including camptothecin, the penicillins, and cyclosporin A, marine fungi also have the potential to produce new chemical scaffolds as leads to potential drugs. Fungi are more phylogenetically diverse than bacteria and have larger genomes that contain many silent biosynthetic gene clusters involved in making bioactive compounds. However, less than 5% of all known fungi have been cultivated under standard laboratory conditions. While the number of reported natural products from marine fungi is steadily increasing, their number is still significantly lower compared to those reported from their bacterial counterparts. Herein, we discuss many varied cytotoxic and anti-infective fungal metabolites isolated from extreme marine environments, including symbiotic associations as well as extreme pressures, temperatures, salinity, and light. We also discuss cultivation strategies that can be used to produce new bioactive metabolites or increase their production. This review presents a large number of reported structures though, at times, only a few of a large number of related structures are shown.

Sacroiliac Joint Dysfunction: Diagnosis and Treatment.

Sacroiliac (SI) joint dysfunction is a common cause of low back pain and accurate diagnosis can be challenging. A complete history and physical examination are critical in differentiating other diagnoses that may have similar signs and symptoms. Positive responses to at least three physical provocation tests suggest SI joint dysfunction, and local anesthetic SI joint blocks can also be useful for confirming the SI joint as the source of pain. Conservative treatment consists of a multimodal program combining patient education, pelvic girdle stabilization with focused stretching, and manipulative therapy. These programs can be performed by physical therapists or clinicians trained in manipulative therapy. Pelvic belts may be beneficial in affected postpartum patients. Patients with symptoms that do not improve with conservative management may benefit from interventional treatment options including intra-articular corticosteroid injections, cooled radiofrequency ablation, or SI joint fusion.

Epidemiology of Hand Fractures and Dislocations in England and Wales Professional Cricketers.

This study describes hand fracture and dislocation injuries in terms of anatomical distribution, incidence and impact on playing time in registered professional adult male players of all 18 First Class England and Wales County Cricket clubs over a five-year period from 2010-2014. Prospectively collected injury surveillance data for 1st and 2nd Team matches (Twenty20, One day and four-day) and training were analysed. There were 109 hand fractures and 53 dislocations. Hand injury was commonest during fielding (60%, 98/162) compared to batting, bowling or wicket-keeping. Exposed parts of the hand including tips of all digits, the index finger, thumb ray and little finger ray were most frequently injured with 78% (125/160) of all injuries where anatomical location was recorded. Match injury incidence for batsmen was highest in four-day matches (0.071 injuries per 1000 overs batted) but for other player roles it was highest in Twenty20 matches (0.587 per 1000 overs bowled). Player unavailability for selection to play was incurred in 82% (89/109) of hand fractures but only 47% (25/53) of dislocations. This study clarifies the hand fracture and dislocation injury burden for this population.

Correction: Antiviral drug discovery: preparing for the next pandemic.

Correction for 'Antiviral drug discovery: preparing for the next pandemic' by Catherine S. Adamson et al., Chem. Soc. Rev., 2021, 50, 3647-3655, DOI: .

Antiviral drug discovery: preparing for the next pandemic.

Clinically approved antiviral drugs are currently available for only 10 of the more than 220 viruses known to infect humans. The SARS-CoV-2 outbreak has exposed the critical need for compounds that can be rapidly mobilised for the treatment of re-emerging or emerging viral diseases, while vaccine development is underway. We review the current status of antiviral therapies focusing on RNA viruses, highlighting strategies for antiviral drug discovery and discuss the challenges, solutions and options to accelerate drug discovery efforts.

Transition Metal Synthetic Ferrimagnets: Tunable Media for All-Optical Switching Driven by Nanoscale Spin Current.

All-optical switching of magnetization has great potential for use in future ultrafast and energy efficient nanoscale magnetic storage devices. So far, research has been almost exclusively focused on rare-earth based materials, which limits device tunability and scalability. Here, we show that a perpendicularly magnetized synthetic ferrimagnet composed of two distinct transition metal ferromagnetic layers, Ni3Pt and Co, can exhibit helicity independent magnetization switching. Switching occurs between two equivalent remanent states with antiparallel alignment of the Ni3Pt and Co magnetic moments and is observable over a broad temperature range. Time-resolved measurements indicate that the switching is driven by a spin-polarized current passing through the subnanometer Ir interlayer. The magnetic properties of this model system may be tuned continuously via subnanoscale changes in the constituent layer thicknesses as well as growth conditions, allowing the underlying mechanisms to be elucidated and paving the way to a new class of data storage devices.

The sugar-responsive circadian clock regulator bZIP63 modulates plant growth.

Adjustment to energy starvation is crucial to ensure growth and survival. In Arabidopsis thaliana (Arabidopsis), this process relies in part on the phosphorylation of the circadian clock regulator bZIP63 by SUCROSE non-fermenting RELATED KINASE1 (SnRK1), a key mediator of responses to low energy. We investigated the effects of mutations in bZIP63 on plant carbon (C) metabolism and growth. Results from phenotypic, transcriptomic and metabolomic analysis of bZIP63 mutants prompted us to investigate the starch accumulation pattern and the expression of genes involved in starch degradation and in the circadian oscillator. bZIP63 mutation impairs growth under light-dark cycles, but not under constant light. The reduced growth likely results from the accentuated C depletion towards the end of the night, which is caused by the accelerated starch degradation of bZIP63 mutants. The diel expression pattern of bZIP63 is dictated by both the circadian clock and energy levels, which could determine the changes in the circadian expression of clock and starch metabolic genes observed in bZIP63 mutants. We conclude that bZIP63 composes a regulatory interface between the metabolic and circadian control of starch breakdown to optimize C usage and plant growth.