Insights into the genetic architecture of Phytophthora capsici root rot resistance in chile pepper (Capsicum spp.) from multi-locus genome-wide association study.

BACKGROUND: Phytophthora root rot, a major constraint in chile pepper production worldwide, is caused by the soil-borne oomycete, Phytophthora capsici. This study aimed to detect significant regions in the Capsicum genome linked to Phytophthora root rot resistance using a panel consisting of 157 Capsicum spp. genotypes. Multi-locus genome wide association study (GWAS) was conducted using single nucleotide polymorphism (SNP) markers derived from genotyping-by-sequencing (GBS). Individual plants were separately inoculated with P. capsici isolates, 'PWB-185', 'PWB-186', and '6347', at the 4-8 leaf stage and were scored for disease symptoms up to 14-days post-inoculation. Disease scores were used to calculate disease parameters including disease severity index percentage, percent of resistant plants, area under disease progress curve, and estimated marginal means for each genotype. RESULTS: Most of the genotypes displayed root rot symptoms, whereas five accessions were completely resistant to all the isolates and displayed no symptoms of infection. A total of 55,117 SNP markers derived from GBS were used to perform multi-locus GWAS which identified 330 significant SNP markers associated with disease resistance. Of these, 56 SNP markers distributed across all the 12 chromosomes were common across the isolates, indicating association with more durable resistance. Candidate genes including nucleotide-binding site leucine-rich repeat (NBS-LRR), systemic acquired resistance (SAR8.2), and receptor-like kinase (RLKs), were identified within 0.5 Mb of the associated markers. CONCLUSIONS: Results will be used to improve resistance to Phytophthora root rot in chile pepper by the development of Kompetitive allele-specific markers (KASP®) for marker validation, genomewide selection, and marker-assisted breeding.

Highly Concentrated Linear Guanidine Amides from the Marine Sipunculid Phascolosoma granulatum.

The chemical diversity of annelids, particularly those belonging to the class Sipuncula, remains largely unexplored. However, as part of a Marine Biodiscovery program in Ireland, the peanut worm Phascolosoma granulatum emerged as a promising source of unique metabolites. The purification of the MeOH/CH2Cl2 extract of this species led to the isolation of six new linear guanidine amides, named phascolosomines A-F (1-6). NMR analysis allowed for the elucidation of their structures, all of which feature a terminal guanidine, central amide linkage, and a terminal isobutyl group. Notably, these guanidine amides were present in unusually high concentrations, comprising ∼3% of the dry mass of the organism. The primary concentration of the phascolosomines in the viscera is similar to that previously identified in linear amides from sipunculid worms and marine fireworms. The compounds from sipunculid worms have been hypothesized to be toxins, while those from fireworms are reported to be defensive irritants. However, screening of the newly isolated compounds for inhibitory bioactivity showed no significant inhibition in any of the assays conducted.

Hypervalent iodine-catalyzed amide and alkene coupling enabled by lithium salt activation.

Hypervalent iodine catalysis has been widely utilized in olefin functionalization reactions. Intermolecularly, the regioselective addition of two distinct nucleophiles across the olefin is a challenging process in hypervalent iodine catalysis. We introduce here a unique strategy using simple lithium salts for hypervalent iodine catalyst activation. The activated hypervalent iodine catalyst allows the intermolecular coupling of soft nucleophiles such as amides onto electronically activated olefins with high regioselectivity.

Association Between Markers of Vulnerability for Cannabis-Related Harms and Source of Supply: Secondary Analysis of a Representative Population Survey.

OBJECTIVE: In 2018, the sale of non-medical cannabis was authorized in the province of Quebec in Canada, within a public monopoly under the Société Québécoise du Cannabis (SQDC). The objective of this study was to offer a description of the cannabis-using population regarding the sources of cannabis supply and to explore whether at-risk individuals are purchasing cannabis at SQDC. METHOD: We used data from a cross-sectional, representative population survey (age >18 years, n = 1799), the Enquête Québécoise sur le Cannabis, which was completed between February and June 2019. Analyses involved adjusted binary logistic regressions, incorporating population weights, to assess 7 potential indicators of harm. RESULTS: The vulnerability profiles of SQDC consumers (47.8%) and those acquiring their cannabis elsewhere (52.2%) were similar in terms of frequency of cannabis use (adjusted odds ratio [aOR] = 0.46; 95% confidence interval [CI] = 0.12-1.67), motivation to use (aOR = 0.62; 95% CI = 0.16-2.46), concomitant consumption of other substances (aOR = 0.80; 95% CI = 0.14-4.75), cannabis-impaired driving behaviours (aOR = 0.93; 95% CI = 0.26-3.36), psychological distress (aOR = 0.99; 95% CI = 0.26-3.79), and problematic cannabis use (aOR = 0.46; 95% CI = 0.13-1.64). However, SQDC consumers were more likely to be aware of the cannabinoid content of the product purchased compared to those who acquired their cannabis from other sources (aOR = 4.12; 95% CI = 1.10-15.40). CONCLUSIONS: No association was detected between the source of cannabis supply and potential vulnerability indicators of cannabis-related harms, but SQDC consumers were more aware of the cannabinoid content of the products purchased. These results suggest that the regulated government supply in Quebec is reaching a substantial portion of those with potential high vulnerability to harm. Whether this knowledge translates into a reduction in the negative consequences related to consumption is still to be determined.

Exploratory Transcriptomic Profiling Reveals the Role of Gut Microbiota in Vascular Dementia.

Stroke is the second most common cause of cognitive impairment and dementia. Vascular dementia (VaD), a cognitive impairment following a stroke, is common and significantly impacts the quality of life. We recently demonstrated via gut microbe transplant studies that the gut microbe-dependent trimethylamine-N-oxide (TMAO) pathway impacts stroke severity, both infarct size and long-term cognitive outcomes. However, the molecular mechanisms that underly the role of the microbiome in VaD have not been explored in depth. To address this issue, we performed a comprehensive RNA-sequencing analysis to identify differentially expressed (DE) genes in the ischemic cerebral cortex of mouse brains at pre-stroke and post-stroke day 1 and day 3. A total of 4016, 3752 and 7861 DE genes were identified at pre-stroke and post-stroke day 1 and day 3, respectively. The Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis indicated pathways of neurodegeneration in multiple diseases, chemokine signaling, calcium signaling, and IL-17 signaling as the key enriched pathways. Inflammatory response genes interleukin-1 beta (Il-1ß), chemokines (C-X-C motif chemokine ligand 10 (Cxcl10), chemokine ligand 2 (Ccl2)), and immune system genes (S100 calcium binding protein 8 (S100a8), lipocalin-2 (Lcn2)) were among the most significantly upregulated genes. Hypocretin neuropeptide precursor (Hcrt), a neuropeptide, and transcription factors such as neuronal PAS domain protein 4 (Npas4), GATA binding protein 3 (Gata3), and paired box 7 (Pax7) were among the most significantly downregulated genes. In conclusion, our results indicate that higher plasma TMAO levels induce differential mRNA expression profiles in the ischemic brain tissue in our pre-clinical stroke model, and the predicted pathways provide the molecular basis for regulating the TMAO-enhanced neuroinflammatory response in the brain.

2Gs and plant architecture: breaking grain yield ceiling through breeding approaches for next wave of revolution in rice (Oryza sativa L.).

Rice is a principal food crop for more than half of the global population. Grain number and grain weight (2Gs) are the two complex traits controlled by several quantitative trait loci (QTLs) and are considered the most critical components for yield enhancement in rice. Novel molecular biology and QTL mapping strategies can be utilized in dissecting the complex genetic architecture of these traits. Discovering the valuable genes/QTLs associated with 2Gs traits hidden in the rice genome and utilizing them in breeding programs may bring a revolution in rice production. Furthermore, the positional cloning and functional characterization of identified genes and QTLs may aid in understanding the molecular mechanisms underlying the 2Gs traits. In addition, knowledge of modern genomic tools aids the understanding of the nature of plant and panicle architecture, which enhances their photosynthetic activity. Rice researchers continue to combine important yield component traits (including 2Gs for the yield ceiling) by utilizing modern breeding tools, such as marker-assisted selection (MAS), haplotype-based breeding, and allele mining. Physical co-localization of GW7 (for grain weight) and DEP2 (for grain number) genes present on chromosome 7 revealed the possibility of simultaneous introgression of these two genes, if desirable allelic variants were found in the single donor parent. This review article will reveal the genetic nature of 2Gs traits and use this knowledge to break the yield ceiling by using different breeding and biotechnological tools, which will sustain the world's food requirements.

Lewis Acid-Catalyzed Halonium Generation for Morpholine Synthesis and Claisen Rearrangement.

We disclose here practical strategies toward the synthesis of morpholines and Claisen rearrangement products based on the divergent reactivity of a common halonium intermediate. These reactions employ widely available alkenes in a Lewis acid-catalyzed halo-etherification process that can then transform them into the desired products with exceptional regioselectivity for both activated and unactivated olefins. Our mechanistic probe reveals an interesting regiochemical kinetic resolution process.

RadioBERT: A deep learning-based system for medical report generation from chest X-ray images using contextual embeddings.

BACKGROUND: Increasing number of chest X-ray (CXR) examinations in radiodiagnosis departments burdens radiologists' and makes the timely generation of accurate radiological reports highly challenging. An automatic radiological report generation (ARRG) system is envisaged to generate radiographic reports with minimal human intervention, ease radiologists' burden, and smoothen the clinical workflow. The success of an ARRG system depends on two critical factors: i) quality of the features extracted by the ARRG system from the CXR images, and ii) quality of the linguistic expression generated by the ARRG system describing the normalities and abnormalities as indicated by the extracted features. Most of the existing ARRG systems miserably fail due to the latter factor and do not generate clinically acceptable reports because they ignore the contextual importance of the medical terms. OBJECTIVES: The advent of contextual word embeddings, like ELMo and BERT, has revolutionized several natural language processing (NLP) tasks. A contextual embedding represents a word based on its context. The main objective of this work is to develop an ARRG system that uses contextual word embeddings to generate clinically accurate reports from CXR images. METHODS: We present an end-to-end deep neural network that uses contextual word representations for generating clinically useful radiological reports from CXR images. The proposed network, termed as RadioBERT, uses DistilBERT for contextual word representation and leverages transfer learning. Additionally, due to the importance of abnormal observations over the normal ones, the network reorders the generated sentences by applying sentiment analysis to keep abnormal descriptions on the top of the generated report. RESULTS: The empirical study consisting of several experiments performed on the OpenI dataset indicates that CNN+Hierarchical LSTM with DistilBERT embedding improves the benchmark performance. We have been able to achieve the following performance scores: BLEU-1 = 0.772, BLEU-2 = 0.770, BLEU-3 = 0.768, BLEU-4 = 0.767, CIDEr = 0.5563, and ROUGE = 0.897. CONCLUSION: The proposed method improves the state-of-the-art performance scores by a substantial margin. It is concluded that the use of word embeddings generated by DistilBERT enhances the performance of hierarchical LSTM for producing clinical reports by significant margin.

Bis-Indole Alkaloids Isolated from the Sponge Spongosorites calcicola Disrupt Cell Membranes of MRSA.

Antimicrobial resistance (AMR) is a global health challenge with methicillin resistant Staphylococcus aureus (MRSA), a leading cause of nosocomial infection. In the search for novel antibiotics, marine sponges have become model organisms as they produce diverse bioactive compounds. We investigated and compared the antibacterial potential of 3 bis-indole alkaloids-bromodeoxytopsentin, bromotopsentin and spongotine A-isolated from the Northeastern Atlantic sponge Spongosorites calcicola. Antimicrobial activity was determined by MIC and time-kill assays. The mechanism of action of bis-indoles was assessed using bacterial cytological profiling via fluorescence microscopy. Finally, we investigated the ability of bis-indole alkaloids to decrease the cytotoxicity of pathogens upon co-incubation with HeLa cells through the measurement of mammalian cell lysis. The bis-indoles were bactericidal to clinically relevant Gram-positive pathogens including MRSA and to the Gram-negative gastroenteric pathogen Vibrio parahaemolyticus. Furthermore, the alkaloids were synergistic in combination with conventional antibiotics. Antimicrobial activity of the bis-indole alkaloids was due to rapid disruption and permeabilization of the bacterial cell membrane. Significantly, the bis-indoles reduced pathogen cytotoxicity toward mammalian cells, indicating their ability to prevent bacterial virulence. In conclusion, sponge bis-indole alkaloids are membrane-permeabilizing agents that represent good antibiotic candidates because of their potency against Gram-positive and Gram-negative bacterial pathogens.

Determination of Alteration in Micromeritic Properties of a Solid Dispersion: Brunauer-Emmett-Teller Based Adsorption and Other Structured Approaches.

The present study is focused on the use of solid dispersion technology to triumph over the solubility-related problems of bexarotene which is currently used for treating various types of cancer and has shown potential inhibitory action on COVID-19 main protease and human ACE2 receptors. It is based on comparison of green locust bean gum and synthetic poloxamer as polymers using extensive mechanistic methods to explore the mechanism behind solubility enhancement and to find suitable concentration of drug to polymer ratio to prepare porous 3rd generation solid dispersion. The prepared solid dispersions were characterized using different studies like X-ray diffraction (XRD), thermal gravimetric analysis (TGA), scanning electron microscopy (SEM), Brunauer-Emmett-Teller (BET), differential scanning calorimetry (DSC), and particle size analysis in order to determine the exact changes occurred in the product which are responsible for enhancing solubility profiles of an insoluble drug. The results showed different profiles for particle size, solubility, dissolution rate, porosity, BET, and Langmuir specific surface area of prepared solid dispersions by using different polymers. In addition to the comparison of polymers, the BET analysis deeply explored the changes occurred in all dispersions when the concentration of polymer was increased. The optimized solid dispersion prepared with MLBG using lyophilization technique showed reduced particle size of 745.7±4.4 nm, utmost solubility of 63.97%, pore size of 211.597 Å, BET and Langmuir specific surface area of 5.6413 m2/g and 8.2757 m2/g, respectively.

Anticancer Effects of Extracts from Three Different Chokeberry Species.

Colon cancer risk appears to be lowered by consumption of a diet rich in fruits and vegetables. Chokeberries are rich in phytochemicals that may act as potent anticancer agents. Phytochemicals that are particularly abundant in chokeberries include anthocyanins and phenolic acids. In this study, we compared the growth inhibitory activity of three chokeberry extracts in HT-29 human colon cancer cells. The three extracts tested were derived from Aronia arbutifolia (red), Aronia prunifolia (purple), and Aronia melanocarpa (black). Cells were incubated with either red, purple, or black chokeberry extracts and cell viability was quantified using the thiazolyl blue tetrazolium bromide (MTT) assay. The black chokeberry extract had the greatest effect in reducing cell proliferation. The extracts were also characterized for total phenols (Folin-Ciocalteu assay), total antioxidant activity (oxygen radical absorbance capacity assay), and levels of bioactive phenolic acids (high-performance liquid chromatography). The growth inhibitory activities of the extracts correlated well with total phenolic content, antioxidant activity, and levels of caffeic and chlorogenic acids. The black chokeberry extract had the greatest level of total phenols, antioxidant activity, and individual phenolic acids. This research suggests that the phenolic profile of foods such as chokeberries can help determine their cancer cell growth inhibitory activity.

Phytohormones: Key players in the modulation of heavy metal stress tolerance in plants.

Heavy metal (HM) stress in plants has received considerable global attention as it threatens sustainable growth in agriculture worldwide. Hence, desperate efforts have been undertaken for combating the effects of this stress in plants. Interestingly, the use of phytohormones in reducing the impact of HM toxicity has gained much momentum in the recent past. Phytohormones act as chemical messengers that improve the HM stress resistance in plants, thus allowing them to retain their growth and developmental plasticity. Their exogenous application as well as manipulation of endogenous levels through precise targeting of their biosynthesis/signaling components is a promising approach for providing a protective shield against HM stress in plants. However, for the successful use of phytohormones for field plants exposed to HM toxicity, in-depth knowledge of the key pathways regulated by them is of prime importance. Hence, the present review mainly summarizes the key conceptual developments on the involvement of phytohormones in the mitigation of HM stress in plants. The role of various genes, proteins, and signaling components involved in phytohormones associated HM stress tolerance and their modulation has also been discussed. Thus, this update will pave the way for improving HM stress tolerance in plants with the advent of phytohormones for sustainable agriculture growth in the future.

Bull's eye sign - A diagnostic clinch in COVID-19 pneumonia.

Although typical imaging findings of COVID-19 pneumonia has been described it may be difficult at times to distinguish it from other viral pneumonias. In the following case series, we describe a typical sign i.e. Bull's-eye sign in COVID-19 pneumonia. As this sign is not associated with any known pulmonary disease, so its presence may help radiologists to differentiate COVID-19 pneumonia from its mimics.

Dengue and COVID-19 Coinfection- A Double Trouble.

COVID 19 since its onset in Wuhan in 2019 has overburdened our existing health resources and infrastructure. Dengue virus has been endemic in Asian countries since decades. Both being viruses with similar clinical profile and overlapping laboratory parameters has posed a great challenge for Asian countries to combat a co epidemic, creating a double burden. We, as clinicians must be more vigilant in diagnosing the patients so that dengue is not missed in this covid pandemic era and does not progress to life threatening dengue shock syndrome. More importantly, we should emphasize on preventive measures for prevention of dengue so that we can reduce the burden on health care system.

Antibiofilm, antiproliferative, antioxidant and antimutagenic activities of an endophytic fungus Aspergillus fumigatus from Moringa oleifera.

An endophytic fungus Aspergillus fumigatus isolated from Moringa oleifera has been evaluated for its various bioactivities. The chloroformic fungal extract exhibited a good antimicrobial as well as antibiofilm activity against various pathogenic microorganisms. It also demonstrated a good antimutagenicity against the reactive carcinogenic ester generating mutagen, 2-aminofluorene (2-AF) with IC50 values of 0.52 mg ml-1 and 0.36 mg ml-1 in case of co-incubation and pre-incubation, respectively. The antiprolifertive activity against different cancer cell lines; such as HCT-15, HeLa A549 and U87-MG showed the IC50 values of 0.061, 0.065 and 0.072 mg ml-1, respectively. The antioxidant activity of fungal extract has been assessed by 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethyl-benzthiazolin-6-sulfonicacid) (ABTS) methods with IC50 values of 40.07 µg and 54.28 µg, respectively. Total phenolics and flavonoid contents have been also determined. Ultra-high performance liquid chromatography (UPLC) of fungal extract revealed the presence of various phenolic compounds (caffeic acid, rutin, ellagic acid, quercetin and kaempferol). Further an attempt has been made to purify the bioactive compounds by column chromatography and GC-MS analysis. The above studies demonstrated a good bioactive potential of endophytic fungus Aspergillus fumigatus and shows the pharmacological importance of an endophytic fungus and justify the need to carry out further studies.

Steering the antitumor drug discovery campaign towards structurally diverse indolines.

Indoline framework is often perpended as a privileged heterocycle present in medicinally valuable compounds of natural and synthetic origin. This review article presents the rational approaches/strategies employed for the design of anticancer indolines along with the structure activity relationship and mechanistic insights revealed in the in-vitro and in-vivo assays. The chemist has always been fascinated towards the indoline ring for the construction of antitumor scaffolds owing to its versatility as evidenced by its existence in scaffolds inducing antiproliferative effects via diverse mechanisms. To the delight of medicinal chemist, the applicability of indoline has also been expanded towards the design of dual inhibitors (multitargeting anticancer agents) as well as PROTACS. Overall, it can be concluded that indoline moiety is a magic bullet and the scaffolds containing this ring are foraying towards detailed preclinical and clinical stage investigations by leaps and bounds.

Depression and Outcomes of Methadone and Buprenorphine Treatment Among People with Opioid Use Disorders: A Literature Review.

Objective: Depression is the most common psychiatric comorbidity among people with opioid use disorders (OUDs). However, whether and how comorbid depression is associated with the outcomes of opioid agonist therapy (OAT) remains poorly understood. The objective of this review was to identify and describe the association between depression and main outcomes (opioid use and treatment retention) of methadone and buprenorphine treatment among people with OUDs. Methods: A literature review was conducted by searching five electronic databases (MEDLINE, PubMed, Embase, Evidence-Based Medicine Reviews [EBMR], and Cumulative Index of Nursing and Allied Health Literature [CINAHL] Complete) from January 1970 to April 2019. Two independent reviewers screened titles and abstracts of the identified records by using pre-established eligibility criteria. Next, full texts were reviewed and studies that met inclusion criteria were selected. Finally, a descriptive synthesis of extracted data was performed. Results: In total, 12,296 records were identified and 18 studies that met inclusion criteria were retained. Of these, six studies reported reduced opioid use and seven reported increased opioid use during methadone or buprenorphine treatment. In addition, three studies reported an increased retention rate and four documented a decreased retention rate during methadone or buprenorphine treatment. The remaining studies did not find any significant association between depression and opioid use or treatment retention. Overall, the evidence did not demonstrate a consistent association between depression and outcomes of methadone or buprenorphine treatment. Conclusions: Although the inconsistent nature of the current evidence prohibited us from drawing definitive conclusions, we posit that the presence of depression among OUDs patients may not always predict negative outcomes related to retention and drug use during the course of OAT. Particularly, the hypothesis that adequate treatment of depression can improve treatment retention is promising and is in line with the call for increased efforts to provide integrated care for comorbid mental health disorders and addiction. Future studies with rigorous methodology are essential to better characterize the complex interplay between depression, OAT, and OUDs.

Catalytic Regio- and Stereoselective Alkene Sulfenoamination for 1,4-Benzothiazine Synthesis.

An alkene sulfenoamination reaction with 2-aminothiophenol is developed using iodide catalysis. This reaction renders access to useful 1,4-benzothiazines with good functional group compatibility including both electron-donating and electron-withdrawing substituents. The reaction is proposed to proceed through an inversion of the polarity of the thiol functionality. Our mechanistic studies reveal that both thiiranium and thiyl radical pathways are plausible and that the disulfide reagent can also function as a viable substrate in this reaction.

Intermolecular alkene difunctionalizations for the synthesis of saturated heterocycles.

Saturated heterocycles are important structural motifs in a range of pharmaceuticals and agrochemicals. As a result of their importance, syntheses of these molecules have been extensively investigated. Despite the progress in this area, the most adopted strategies are still often characterized with inefficiency or relying on functionalizations with specialized precursors and pre-existing cores. This review highlights a dynamic synthetic strategy for the direct synthesis of saturated heterocycles from intermolecular alkene difunctionalizations. These coupling processes are highly modular, and therefore, offer perhaps the most convenient means to prepare diverse heterocyclic structures in compound libraries for bioactivity evoluations.

Practical mixed methods strategies used to integrate qualitative and quantitative methods in community-based primary health care research.

BACKGROUND: Mixed methods (MM) are common in community-based primary health care (CBPHC) research studies. Several strategies have been proposed to integrate qualitative and quantitative components in MM, but they are seldom well conceptualized and described. The purpose of the present review was to identify and describe practical MM strategies and combinations of strategies used to integrate qualitative and quantitative methods in CBPHC research. METHODS: A methodological review with qualitative synthesis (grouping) was performed. Records published in English in 2015 were retrieved from the Scopus bibliographic database. Eligibility criteria were: CBPHC empirical study, MM research with detailed description of qualitative and quantitative methods and their integration. Data were extracted from included studies and grouped using a conceptual framework comprised of three theoretical types of MM integration, the seven combinations of these types and nine practical strategies (three per type of integration) and multiple combinations of strategies. RESULTS: Among the 151 articles reporting CBPHC and MM studies retrieved, 54 (35.7%) met the inclusion criteria for this review. The included studies provided examples of the three theoretical types of MM integration, the seven combinations of these types as well as the nine practical strategies. Overall, 15 combinations of these strategies were observed. No emerging strategy was observed that was not predicted by the conceptual framework. CONCLUSIONS: This review can provide guidance to CBPHC researchers for planning, conducting and reporting practical strategies and combinations of strategies used for integrating qualitative and quantitative methods in MM research.