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The genus Coleus is revised for DR. Congo, Rwanda, Burundi, based on herbarium taxonomy. Ninety-five taxa are reported (89 species, 1 subspecies, 5 varieties). Fifteen new species and one new variety are described (Coleus duvigneaudii, C. esculentus var. kolweziensis, C. hildei, C. kaminaensis, C. kundelunguensis, C. linarioides, C. lisowskii, C. marunguensis, C. minusculus, C. mitwabaensis, C. mystax, C. pengbelensis, C. piscatorum, C. pseudoschizophyllus, C. ruziziensis and C. zigzag). Fourteen species are newly recorded in DR. Congo and two species are newly recorded in Burundi. Four new combinations are made (Coleus betonicifolius var. kasomenensis, C. esculentus var. densus, C. esculentus var. primulinus and C. parvifolius). Ten names are lectotypified. One name is neotypified. Thirteen new synonyms are reported. Particular attention is paid to the Coleus bojeri complex. Three names are resurrected to accommodate the extensive variation patterns in Central Africa (C. chevalieri, C. collinus and C. heterotrichus); their distribution in Africa is outlined and the circumscription of C. bojeri is amended accordingly. Fifteen taxa are endemic to the study region. A determination key is provided.

Infant formula milk (IFM) is increasingly utilized as a substitute for natural breastfeeding despite the fact that breast milk has been always recognized as the optimal nourishment method. While IFMs are fortified with essential nutrients that are crucial for proper growth, they can also harbor non-essential toxic metal contaminants from various sources during the production process. Given the heightened vulnerability of newborns to such contaminants, it is imperative to thoroughly analyze, evaluate, and minimize the toxicity associated with the consumption of such IFMs. However, classical approaches to date, have been always adopted for assessing such risks by finding first the analytical concentration of metals in the IFMs followed by multiplying it by the average daily powder intake (ADI) then dividing by the average infant weight. The outcome is then compared to an established standard such a PTWI to assess the extent of toxicity. The drawback with such studies is the use of a fixed ADI for all samples as if all samples have the same and exact preparation directions while using somewhat different infant masses.Accordingly, this study aims at assessing the toxic risk amongst newborns from IFM consumption through the identification and application of various highly important and toxicity-contributing parameters from each IFM and its directions of preparation label separately which are discussed here for the first time while providing comparisons between the classical approach versus our new approach to highlight its importance.Seventy-three IFMs (0–6 months) were analyzed for lead (Pb), cadmium (Cd), arsenic (As), and aluminum (Al) levels and unlike previous studies, this work incorporated various feeding parameters from each IFM for calculating the intakes thus, revealing potential toxicity risks even in IFMs that are considered safe by the classical approach. Metal contamination was significant, with 97.3 % of samples containing detectable Pb, 41.1 % Cd, 16.4 % As, and 93.2 % Al while highlighting Pb in exceeding its maximum allowable level (MAL). This novel approach, which considers new diverse feeding schedules/parameters that are ironically suggested by manufacturers that have been previously overlooked elsewhere, emphasized IFMs' potential as sources of heightened metal toxicity in comparison to classical approaches. Results highlighted Pb and Al as major concerns, with As and Cd of lesser concern. Findings also emphasized the importance of such new parameters for safeguarding newborn health and should be payed attention to by caregivers. The study strongly and highly recommends adherence to minimum feeding schedules (MFS) and proper scooping techniques to reduce newborn exposure to toxic metals. It also suggests continuous monitoring and stricter regulations by health authorities at the production level of such products so as to provide a safer commodity in the first degree and to also provide better and somewhat uniform and specific feeding labels and precautions on such products.

Decades of wheat breeding have provided growers with numerous high-yielding options, but it is unknown if these yield improvements are likewise characterized with improved nitrogen use efficiency (NUE). Fertilizer nitrogen (N) is an ever-increasing expense, so improving NUE by reducing the requirement for N fertilizer without risking yield and quality is necessary. The goal of our research is to identify cultivars and associated traits that may improve NUE while maintaining productivity. We compared 25 spring wheat cultivars over a three-year period (2020, 2021, 2022) at two field sites differing in background soil N level for the ability to use fertilizer-N and allocate it to the grain. To do so, we employed the 15N stable isotope technique to trace the flow of fertilizer-N and determine the 15N recovery efficiency (15NRE). The 15NRE in the grain averaged 25.0% at the higher soil N site, and 15.5% at the lower soil N site. At the higher soil N site only, dwarfing alleles (Rht-B1b) were associated with greater 15NRE. Grain 15NRE was positively associated with yield, grain N content, and the 15N harvest index (15NHI) at the high soil N environment, but never at the low soil N environment. Our findings support the notion that the genetic development of high yielding semi-dwarf cultivars also translates into an improved ability to recover fertilizer-N—but this outcome is only expressed only under rich soil N conditions. Cultivars that simultaneously produced higher 15NRE and yields, grain N, or 15NHI differed by environment; possibly suggesting different mechanisms for improving crop NUE depending on background soil N level. Ultimately, cultivar-specific 15NRE information, including that presented here, will be useful breeders to design new crosses and approaches aimed at increasing NUE for spring wheat.

The intestinal microbiota is an important environmental factor implicated in CRC development. Intriguingly, modulation of DNA methylation by gut microbiota has been reported in preclinical models, although the relationship between tumor-infiltrating bacteria and CIMP status is currently unexplored. In this study, we investigated tumor-associated bacteria in 203 CRC tumor cases and validated the findings using The Cancer Genome Atlas datasets. We assessed the abundance of Bacteroides fragilis, Escherichia coli, Fusobacterium nucleatum, and Klebsiella pneumoniae through qPCR analysis and observed enrichment of all four bacterial species in CRC samples. Notably, except for E. coli, all exhibited significant enrichment in cases of CIMP. This enrichment was primarily driven by a subset of cases distinguished by high levels of these bacteria, which we labeled as “Superhigh”. The bacterial Superhigh status showed a significant association with CIMP (odds ratio 3.1, p-value = 0.013) and with MLH1 methylation (odds ratio 4.2, p-value = 0.0025). In TCGA CRC cases (393 tumor and 45 adj. normal), bacterial taxa information was extracted from non-human whole exome sequencing reads, and the bacterial Superhigh status was similarly associated with CIMP (odds ratio 2.9, p

[CD8.sup.+] T cells destroy insulin-producing pancreatic [beta] cells in type 1 diabetes through HLA class I- restricted presentation of self-antigens. Combinatorial peptide library screening was used to produce a preferred peptide recognition landscape for a patient-derived T cell receptor (TCR) that recognized the preproinsulin-derived (PPI-derived) peptide sequence LWMRLLPLL in the context of disease risk allele HLA A*24:02. Data were used to generate a strong superagonist peptide, enabling production of an autoimmune HLA A*24:02-peptide-TCR structure by crystal seeding. TCR binding to the PPI epitope was strongly focused on peptide residues Arg4 and Leu5, with more flexibility at other positions, allowing the TCR to strongly engage many peptides derived from pathogenic bacteria. We confirmed an epitope from Klebsiella that was recognized by PPI-reactive T cells from 3 of 3 HLA A*24:02+ patients. Remarkably, the same epitope selected T cells from 7 of 8 HLA A*24* healthy donors that cross-reacted with PPI, leading to recognition and killing of HLA A*24:02+ cells expressing PPI. These data provide a mechanism by which molecular mimicry between pathogen and self-antigens could have resulted in the breaking of self-tolerance to initiate disease., Introduction Multiple lines of evidence show that type 1 diabetes (T1D) develops due to [CD8.sup.+] T cell-mediated destruction of insulin-producing pancreatic [beta] cells. Human leukocyte antigen class I (HLA-I), the [...]

Abstract Background Muscle aging is associated with a consistent decrease in the ability of muscle tissue to regenerate following intrinsic muscle degradation, injury or overuse. Age‐related imbalance of protein synthesis and degradation, mainly regulated by AKT/mTOR pathway, leads to progressive loss of muscle mass. Maintenance of anabolic and regenerative capacities of skeletal muscles may be regarded as a therapeutic option for sarcopenia and other muscle wasting diseases. Our previous studies have demonstrated that BIO101, a pharmaceutical grade 20‐hydroxyecdysone, increases protein synthesis through the activation of MAS receptor involved in the protective arm of renin‐angiotensin‐aldosterone system. The purpose of the present study was to assess the anabolic and pro‐differentiating properties of BIO101 on C2C12 muscle cells in vitro and to investigate its effects on adult and old mice models in vivo. Methods The effects of BIO101 on C2C12 differentiation were assessed using myogenic transcription factors and protein expression of major kinases of AKT/mTOR pathway by Western blot. The in vivo effects of BIO101 have been investigated in BIO101 orally‐treated (50 mg/kg/day) adult mice (3 months) for 28 days. To demonstrate potential beneficial effect of BIO101 treatment in a sarcopenic mouse model, we use orally treated 22‐month‐old C57Bl6/J mice, for 14 weeks with vehicle or BIO101. Mice body and muscle weight were recorded. Physical performances were assessed using running capacity and muscle contractility tests. Results Anabolic properties of BIO101 were confirmed by the rapid activation of AKT/mTOR, leading to an increase of C2C12 myotubes diameters (+26%, P

Abstract Carbon sequestration in grasslands has been proposed as an important means to offset greenhouse gas emissions from ruminant systems. To understand the potential and limitations of this strategy, we need to acknowledge that soil carbon sequestration is a time-limited benefit, and there are intrinsic differences between short- and long-lived greenhouse gases. Here, our analysis shows that one tonne of carbon sequestrated can offset radiative forcing of a continuous emission of 0.99 kg methane or 0.1 kg nitrous oxide per year over 100 years. About 135 gigatonnes of carbon is required to offset the continuous methane and nitrous oxide emissions from ruminant sector worldwide, nearly twice the current global carbon stock in managed grasslands. For various regions, grassland carbon stocks would need to increase by approximately 25% − 2,000%, indicating that solely relying on carbon sequestration in grasslands to offset warming effect of emissions from current ruminant systems is not feasible.

BackgroundSuicide is a leading cause of death worldwide, and nonfatal suicide attempts, which occur far more frequently, are a major source of disability and social and economic burden. Both have substantial genetic etiology, which is partially shared and partially distinct from that of related psychiatric disorders.MethodsWe conducted a genome-wide association study (GWAS) of 29,782 suicide attempt (SA) cases and 519,961 controls in the International Suicide Genetics Consortium (ISGC). The GWAS of SA was conditioned on psychiatric disorders using GWAS summary statistics via multitrait-based conditional and joint analysis, to remove genetic effects on SA mediated by psychiatric disorders. We investigated the shared and divergent genetic architectures of SA, psychiatric disorders, and other known risk factors.ResultsTwo loci reached genome-wide significance for SA: the major histocompatibility complex and an intergenic locus on chromosome 7, the latter of which remained associated with SA after conditioning on psychiatric disorders and replicated in an independent cohort from the Million Veteran Program. This locus has been implicated in risk-taking behavior, smoking, and insomnia. SA showed strong genetic correlation with psychiatric disorders, particularly major depression, and also with smoking, pain, risk-taking behavior, sleep disturbances, lower educational attainment, reproductive traits, lower socioeconomic status, and poorer general health. After conditioning on psychiatric disorders, the genetic correlations between SA and psychiatric disorders decreased, whereas those with nonpsychiatric traits remained largely unchanged.ConclusionsOur results identify a risk locus that contributes more strongly to SA than other phenotypes and suggest a shared underlying biology between SA and known risk factors that is not mediated by psychiatric disorders.

Apigenin-7-O-(4′′-feruloyl)-β-D-glucopyranoside (1) were isolated from the methanol extract of aerial part of Echinops gracilis, together with apigenin-7-O-(4′′-trans-p-hydroxycinnamoyl)-β-D-glucopyranoside (2) and apigenin-7-O-β-D-glucopyranoside (3). Compound (1) previously displayed antioxidant and antibacterial activity. The present study aims at evaluating the antiproliferative potential of flavonoids, isolated from the aerial part of E. gracilis O. Hoffm. The effect of compounds (1), (2) and (3) on the viability of HeLa cells was determined by the method of 3-(4,5-dimethythiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay at different concentrations. The ability of compounds to induce the cell death was evaluated by using acridine orange/ethidium bromide (AO/EtBr) staining. Compound (1) induced an effective change in the cell viability of HeLa cells with IC50 concentration value of 27.36 µgmL-1. Induction of cell death alteration in cell morphology and cancer cell population was observed in cells treated with compound (1), which makes it behave as a potent synergistic antiproliferative agent against HeLa cells.

Abstract Background Sarcopenia is an age‐related skeletal muscle disorder characterized by loss of muscle mass and strength leading to mobility disability. 20‐Hydroxyecdysone (20E) is a polyhydroxylated plant steroid that demonstrates pharmacological effects in many disease animal models including ageing/sarcopenia. BIO101 is a 20E purified investigational drug (≥97%) that previously demonstrated good toxicology profiles in rat and dog. BIO101 is evaluated in healthy young and older adults in a Phase 1 study. Methods This study is a Single Ascending Dose (SAD) followed by a 14‐day Multiple Ascending Dose (MAD). In SAD, BIO101 was administered orally to 16 young adults at doses from 100 to 1400 mg and to 8 older adults (age ≥65 years) at 1400 mg. In MAD, doses of 350 mg once daily (qd), 350 mg twice daily (bid) and 450 mg bid were administered to 10 older adults. The primary objective was to evaluate safety and pharmacokinetics (PK), including dosing of circulating metabolites. Pharmacodynamic effects were investigated with regard to myostatin, procollagen‐III‐amino‐terminal propeptide (PIIINP), myoglobin, creatine‐kinase Muscle Brain (CKMB), renin and aldosterone plasma/serum levels. Results BIO101 showed a good safety profile with only mild to moderate adverse events and a satisfactory pharmacokinetic profile. In SAD, at 100 mg to 1400 mg, mean Cmax and areas under the curve increased less than dose‐proportionally. Mean half‐life was short (2.4–4.9 h), and mean renal clearance was comparable in all doses (4.05–5.05 L/h). Mean plasma exposure was slightly lower in older adults (22% lower for Cmax and 13%–15% lower for AUCs) compared with young subjects. In MAD, 350 and 450 mg bid led to a slight accumulation over 14 days (mean ratio of accumulation [Rac] of 1.31 in both cohorts). Reduction of biomarkers (myoglobin, CK‐MB) mean serum levels (vs. baseline) was observed at 450 mg bid. Two major metabolites of 20E (14‐deoxy‐20‐hydroxyecdysone and 14‐deoxypoststerone) were identified and quantified. Conclusions BIO101 shows a good safety and pharmacokinetic profile that led to the selection of doses for the subsequent interventional clinical trials of Phase 2 in age‐related sarcopenia (SARA‐INT) and Phase 3 in Covid‐19 (COVA).

Canary seed flour is a new food ingredient that the United States Food and Drug Administration (FDA) and Health Canada recently granted Generally Regarded as Safe (GRAS) status. Stability in nutritional composition and functional properties is an essential characteristic of food ingredients for consistency in nutritional quality and performance in processing. This work assessed the effect of genotypic and environmental variation on the nutritional (protein, starch, amylose, oil, dietary fiber, minerals and fat-soluble vitamins) and pasting (as measured in viscosity (peak, trough, breakdown, final, and setback), peak time, and pasting temperatures) properties of Canary seed. The samples included four Canary seed varieties grown in randomized complete block design experiments at one location for two growing seasons. In general, the nutritional composition of Canary seed flour was not affected by genotype, growing year, and their interaction except for starch content, which was significantly affected by the growing year (p < 0.0001), and iron content, which was affected by genotypic variation (p < 0.0001). The pasting properties of Canary seed flour were significantly (p < 0.001) affected by both genotypic and growing year variation but not their interaction. Our results suggest that the food industry should measure starch and iron content prior to processing to ensure consistency in nutritional labeling. Also, for those applications where starch pasting properties are essential, the manufacturer should consider measuring the RVA pasting viscosities for every batch of raw material. The results have provided the baseline knowledge of which nutritional or functional properties of Canary seed flour can be improved through breeding and agronomy programs to ensure the reliability of Canary seed as an ingredient.

DNA methylation is an epigenetic process altered in cancer and ageing. Age-related methylation drift can be used to estimate lifespan and can be influenced by extrinsic factors such as diet. Here, we report that non-pathogenic microbiota accelerate age-related methylation drift in the colon when compared with germ-free mice. DNA methylation analyses showed that microbiota and IL10KO were associated with changes in 5% and 4.1% of CpG sites, while mice with both factors had 18% alterations. Microbiota, IL10KO, and their combination altered 0.4%, 0.4%, and 4% of CpG island methylation, respectively. These are comparable to what is seen in colon cancer. Ageing changes were accelerated in the IL10KO mice with microbiota, and the affected genes were more likely to be altered in colon cancer. Thus, the microbiota affect DNA methylation of the colon in patterns reminiscent of what is observed in ageing and colorectal cancer.

Fukutin-related protein (FKRP, MIM ID 606596) variants cause a range of muscular dystrophies associated with hypo-glycosylation of the matrix receptor, α-dystroglycan. These disorders are almost exclusively caused by homozygous or compound heterozygous missense variants in the FKRP gene that encodes a ribitol phosphotransferase. To understand how seemingly diverse FKRP missense mutations may contribute to disease, we examined the synthesis, intracellular dynamics, and structural consequences of a panel of missense mutations that encompass the disease spectrum. Under non-reducing electrophoresis conditions, wild type FKRP appears to be monomeric whereas disease-causing FKRP mutants migrate as high molecular weight, disulfide-bonded aggregates. These results were recapitulated using cysteine-scanning mutagenesis suggesting that abnormal disulfide bonding may perturb FKRP folding. Using fluorescence recovery after photobleaching, we found that the intracellular mobility of most FKRP mutants in ATP-depleted cells is dramatically reduced but can, in most cases, be rescued with reducing agents. Mass spectrometry showed that wild type and mutant FKRP differentially associate with several endoplasmic reticulum (ER)-resident chaperones. Finally, structural modelling revealed that disease-associated FKRP missense variants affected the local environment of the protein in small but significant ways. These data demonstrate that protein misfolding contributes to the molecular pathophysiology of FKRP-deficient muscular dystrophies and suggest that molecules that rescue this folding defect could be used to treat these disorders.

No abstract available.

Abstract Recent advances in light‐responsive materials enabled the development of devices that can wirelessly activate tissue with light. Here it is shown that solution‐processed organic heterojunctions can stimulate the activity of primary neurons at low intensities of light via photochemical reactions. The p‐type semiconducting polymer PDCBT and the n‐type semiconducting small molecule ITIC (a non‐fullerene acceptor) are coated on glass supports, forming a p–n junction with high photosensitivity. Patch clamp measurements show that low‐intensity white light is converted into a cue that triggers action potentials in primary cortical neurons. The study shows that neat organic semiconducting p–n bilayers can exchange photogenerated charges with oxygen and other chemical compounds in cell culture conditions. Through several controlled experimental conditions, photo‐capacitive, photo‐thermal, and direct hydrogen peroxide effects on neural function are excluded, with photochemical delivery being the possible mechanism. The profound advantages of low‐intensity photo‐chemical intervention with neuron electrophysiology pave the way for developing wireless light‐based therapy based on emerging organic semiconductors.

This case report presents a perplexing case of Actinomycosis infection in a patient undergoing routine surveillance after surgical treatment of endometrial cancer 10 years earlier. Her history was significant for recurrence of endometrial cancer in the vaginal vault after one year which was treated with radiation therapy.During routine surveillance follow up, a periurethral mass was noted on bimanual and speculum examination approximately 9 years after the last recurrence. It was suspected to be a recurrence of endometrial cancer based on the appearance of lesion and the patient's history of recurrent cancer. The mass was biopsied and sent only for tissue pathology, which was resulted as Actinomyces on background of necrotic tissue and absence of malignant cells.The patient was started on oral antimicrobial agents effective against Actinomycosis with the intention of repeating the bimanual and speculum examination and performing a CT scan after an appropriate duration of treatment to evaluate for resolution of mass indicating treatment of cure.This case demonstrates the need to consider the possibility of pelvic actinomycosis infection in patients with radiation induced injury to vaginal mucosa in absence of other known risk factors.

Advances in genomics have expedited the improvement of several agriculturally important crops but similar efforts in wheat (Triticum spp.) have been more challenging. This is largely owing to the size and complexity of the wheat genome1, and the lack of genome-assembly data for multiple wheat lines2,3. Here we generated ten chromosome pseudomolecule and five scaffold assemblies of hexaploid wheat to explore the genomic diversity among wheat lines from global breeding programs. Comparative analysis revealed extensive structural rearrangements, introgressions from wild relatives and differences in gene content resulting from complex breeding histories aimed at improving adaptation to diverse environments, grain yield and quality, and resistance to stresses4,5. We provide examples outlining the utility of these genomes, including a detailed multi-genome-derived nucleotide-binding leucine-rich repeat protein repertoire involved in disease resistance and the characterization of Sm16, a gene associated with insect resistance. These genome assemblies will provide a basis for functional gene discovery and breeding to deliver the next generation of modern wheat cultivars.

New therapies in a publicly funded healthcare system are first appraised by health technology assessment agencies that provide funding recommendations to the payers. Treatment with Chimeric Antigen Receptor-T cell (CAR-T) therapy is revolutionizing the management of patients with relapsed/refractory aggressive B-cell lymphoma by providing an effective alternative to the standard of care. Yet, the implementation of CAR-T treatment has a substantial impact on the healthcare system due to its high cost, complex manufacturing process, and requirement for highly specialized services and expertise. CAR-T Cells, as a “living drug”, are fundamentally different from usual medications, and their approvals and funding recommendations pose unique challenges to the health technology agency. In this paper, we explore the specific challenges that face the health technology agencies in reviewing reimbursement recommendations for CAR-T therapy. We take a Canadian perspective and use CAR-T treatment of relapse/refractory aggressive B-cell lymphoma as an example.

Acting as GTPase activating proteins promoting the silencing of activated G-proteins, regulators of G protein signaling (RGSs) are generally considered negative modulators of cell signaling. In the CNS, the expression of RGS4 is altered in diverse pathologies and its upregulation was reported in astrocytes exposed to an inflammatory environment. In a model of cultured cortical astrocytes, we herein investigate the influence of RGS4 on intracellular calcium signaling mediated by type 5 metabotropic glutamate receptor (mGluR5), which is known to support the bidirectional communication between neurons and glial cells. RGS4 activity was manipulated by exposure to the inhibitor CCG 63802 or by infecting the cells with lentiviruses designed to achieve the silencing or overexpression of RGS4. The pharmacological inhibition or silencing of RGS4 resulted in a decrease in the percentage of cells responding to the mGluR5 agonist DHPG and in the proportion of cells showing typical calcium oscillations. Conversely, RGS4-lentivirus infection increased the percentage of cells showing calcium oscillations. While the physiological implication of cytosolic calcium oscillations in astrocytes is still under investigation, the fine-tuning of calcium signaling likely determines the coding of diverse biological events. Indirect signaling modulators such as RGS4 inhibitors, used in combination with receptor ligands, could pave the way for new therapeutic approaches for diverse neurological disorders with improved efficacy and selectivity.