Asymmetric Cascade Dearomatization-Cyclization Reaction of Tryptamines with ß,γ-Alkynyl-α-imino Esters: Access to Hexahydropyrrolo[2,3-b]indole-Containing Tetrasubstituted α-Amino Allenoates.

An organocatalytic enantio- and diastereoselective synthesis of hexahydropyrrolo[2,3-b]indole-containing tetrasubstituted α-amino allenoates, exhibiting both axial and central chirality, has been accomplished via cascade dearomatization-cyclization reaction. The γ-addition to ß,γ-alkynyl-α-imino esters provides a library of densely substituted highly enantioenriched allenes in high yields and excellent stereoselectivities. In addition, the scope of this methodology has been extended to tryptophol as well. A scale-up reaction and synthetic transformations of the products were performed to demonstrate the practical usefulness of this approach.

Aetiology and diagnostic utility of serum ascites albumin gradient in children with ascites.

BACKGROUND: Ascites in children is multifactorial and serum ascites albumin gradient (SAAG) ≥1.1 helps differentiate portal hypertension (PHTN) related from non-PHTN ascites. AIMS: We evaluated the aetiology and diagnostic accuracy of SAAG in children with ascites. METHODS: Children with ascites were retrospectively evaluated. Etiological diagnosis was based on clinical presentation and investigations. All cases with ascitic fluid analysis and a definite diagnosis were included for calculating the utility of SAAG. RESULTS: We enrolled 878 children (568[64.7%] boys). Majority were PHTN related (638[72.7%]) and secondary to acute viral hepatitis (98,15.4%), acute liver failure (185,29%), chronic liver disease (276,43.3%) and Budd-Chiari syndrome (79,12.4%). Other causes included tubercular (46,5.2%), pancreatic (32,3.6%), chylous (20,2.3%), biliary (12,1.4%), pseudoascites (16,1.8%), infections (46,5.2%), nephrotic (26,2.9%), malignancy (23,2.6%), cardiac (9,1.0%) and others (10,1%). SAAG (n = 305) correctly differentiated PHTN and non-PHTN ascites in 272 (89.2%) cases, with a high sensitivity (97%), specificity (93%) and diagnostic accuracy (95.8%). Reasons for inaccurate SAAG included mixed ascites (n = 9), different day serum and ascitic fluid albumin estimation (n = 5), serum albumin ≤1.1 g/dL (n = 2), chylous ascites (n = 3), hypergammaglobulinemia (n = 1), albumin infusions (n = 1) and unexplained (n = 12). CONCLUSIONS: Nearly 27% children had non-PHTN related ascites. SAAG differentiates PHTN from non-PHTN ascites with a diagnostic accuracy of 95%.

Organocatalytic Asymmetric Cascade Michael-Acyl Transfer Reaction between 2-Fluoro-1,3-diketones and 2-Hydroxynitrostyrenes.

An organocatalytic asymmetric cascade Michael-acyl transfer reaction of 2-hydroxynitrostyrenes and monofluorinated ß-diketones has been developed employing a cooperative catalytic system. A combination of quinine-derived bifunctional squaramide catalyst and achiral hydrogen bond donor cocatalyst was found to be the most effective for this reaction and provided the fluorinated acyl transfer products in high yields with good diastereo- and excellent enantioselectivities. Synthetic transformations have been demonstrated, including the synthesis of functionalized 2,3-dihydrobenzofurans and 1-pyrroline.

Stainless steel vs. titanium miniscrew implants: Evaluation of stability during retraction of maxillary and mandibular anterior teeth.

OBJECTIVES: This study was aimed to compare the stability of stainless steel and titanium miniscrew implants of the same diameter and length during en masse retraction of maxillary and mandibular anterior teeth. MATERIALS AND METHODS: Forty miniscrew implants (1.3 mm diameter and 8 mm length) were placed in 10 patients (20 titanium and 20 stainless steel). Stability was checked at insertion (T0), at one month (T1), and at sixth months (T2) and the amount of retraction was recorded in millimeters. RESULTS: Titanium and stainless steel implants were equally stable at the time of insertion. At T1, three titanium miniscrew implants showed grade 2 mobility, whereas seven stainless steel miniscrew implants showed grade 2 mobility. For T2, none of the titanium miniscrew implants had grade 2 mobility while four stainless steel miniscrew implants resulted in grade 2 mobility. Both had an equal frequency of grade 3 and grade 4 mobility. However, the difference in the stability was not statistically significant. No statistical significance was found when the amount of retraction achieved by titanium and stainless steel miniscrew implants was compared between the maxillary and mandibular arches. CONCLUSION: Both titanium and stainless steel miniscrew implants provide good anchorage and remain stable during en masse retraction of maxillary and mandibular anterior teeth. Thus, both miniscrews are clinically effective.

Natural alkaloids targeting EGFR in non-small cell lung cancer: Molecular docking and ADMET predictions.

The phytochemicals contribute to the processes of protection and interaction by acting as antioxidants, anti-mutagens, anticarcinogens, and antimicrobial agents. Among the diverse families of phytoconstituents, alkaloids play an essential role in medicine. These are low-molecular-mass compounds containing nitrogen and are generally alkaline. In this study, in silico molecular docking was performed using AutoDock Vina for thirty-one alkaloids against epidermal growth factor receptor (EGFR). Erlotinib was used as a reference ligand for this study. Erlotinib has been linked to various serious side effects over the past decade, including folliculitis, diarrhoea, paronychia, fatigue, conjunctivitis, ectopion, and epiphora of the lower eyelids. This study found sanguinarine (-10.7 kcal mol-1) to be the most potent inhibitor of EGFR as compared to erlotinib (-7.5 kcal mol-1). Other alkaloids namely, isocolumbin (-9.3 kcal mol-1), lunamarine (-9.1 kcal mol-1), ajmaline (-8.6 kcal mol-1), magnoflorine (-8.6 kcal mol-1) and jatrorrhizine (-8.5 kcal mol-1) also showed potent inhibition against EGFR, but the stability of these molecules with EGFR was less than sanguinarine and more than erlotinib. These were stable and ideal pharmaceutical alkaloids because of their significant interactions, minimal Gibbs free energy, safety, effectiveness and selectivity. Amongst the 31 alkaloids subjected to ADMET prediction, 29 alkaloids followed Lipinski's rule of five. These 29 alkaloids were predicted to have high bioavailability, high lead-likeness score, low toxicity and were easier to synthesize. Compared to erlotinib, other molecules showed less or no inhibition of EGFR. The six named compounds listed above may be potent inhibitors for EGFR mutated cancers, as for example non-small cell lung cancer, colorectal cancer, and pancreatic cancer.

Exploring Phytochemicals from Himalayan Medicinal Plants as Novel Therapeutic Agents.

Over-prescription of medicines leads to some crucial health issues like resistance, non-specificity, etc. Therefore, a human consumes various natural foods, therapeutics, and nutritional supplements to combat this problem. Various therapeutic properties of secondary metabolites, such as anticancer, anti-inflammatory, and antibacterial properties, are important in drug discovery and medicinal application. These natural products have replaced synthetic materials, resulting in a great deal of sustainability, rational use, and preservation of biodiversity. This review described the potential therapeutic applications of secondary plant metabolites found in Himalayan Indian plants. The database contains 45 plants to treat various diseases, such as cancer, inflammation, and microbial infections. Besides authorized ITIS names, it includes Hindi names, family names, and active constituents. The most important information about the molecules can be found in the hyperlinks for the active constituents. It includes structures (two-dimensional and threedimensional), names and identifiers, chemical and physical properties, spectral information, biochemistry, literature and patents. The review also references various phytochemicals responsible for preventing COVID-19. Despite several challenges in manufacturing natural products, researchers may conduct research to produce successful medicines with few side effects.

Prevalence and predictive factors of undernutrition and low bone mineral density in children with chronic pancreatitis.

BACKGROUND: Malnutrition and bone disease are common in adults with chronic pancreatitis (CP). We studied the nutritional status and bone mineral density (BMD) of children with CP and the factors predicting them. METHODS: CP children were prospectively evaluated with a detailed questionnaire, anthropometry, 25-hydroxy vitamin D, fecal elastase and BMD [total body less head (TBLH), spine and hip] by dual energy x-ray absorptiometry. Body mass index (BMI) Z score of -1 to -1.9, -2 to -2.9 and <-3 was taken as mild, moderate and severe malnutrition respectively. Low BMD and osteoporosis were defined as per International Society for Clinical Densitometry. RESULTS: 83 children (46 boys, 14[4.3-21]years) with CP were enrolled. Majority had Cambridge IV (51,62.2%) or III (15,18.3%) changes. 34(41%) had undernutrition (mild-37.3%, moderate-2.4%, severe-1.2%). Overweight and obesity were present in 3.6% and 1.2% cases. BMI had a significant correlation with haemoglobin, serum albumin, percentage body fat and BMD. A majority had low fecal elastase (69 [84.1%], <100 µg/g) and vitamin D deficiency (70[84.3%],<20 ng/ml). 9 cases had a history of fractures. 14/75(18.6%) cases had low TBLH-BMD and this group had a lower BMI (-1.3[-1.9 to 0.34] vs 0.8 [-2.1 to 5.50; p = 0.03) than patients with normal BMD. There was no difference in age, disease duration, vitamin D, fecal elastase and Cambridge grade between normal and low BMD. CONCLUSIONS: 41% CP children have undernutrition with a majority having mild undernutrition. Nearly 20% have low BMD, with osteoporosis in none. Subjects with low BMI have lower BMD and percentage body fat.

Integrated genomic view of SARS-CoV-2 in India.

Background: India first detected SARS-CoV-2, causal agent of COVID-19 in late January 2020, imported from Wuhan, China. From March 2020 onwards, the importation of cases from countries in the rest of the world followed by seeding of local transmission triggered further outbreaks in India. Methods: We used ARTIC protocol-based tiling amplicon sequencing of SARS-CoV-2 (n=104) from different states of India using a combination of MinION and MinIT sequencing from Oxford Nanopore Technology to understand how introduction and local transmission occurred. Results: The analyses revealed multiple introductions of SARS-CoV-2 genomes, including the A2a cluster from Europe and the USA, A3 cluster from Middle East and A4 cluster (haplotype redefined) from Southeast Asia (Indonesia, Thailand and Malaysia) and Central Asia (Kyrgyzstan). The local transmission and persistence of genomes A4, A2a and A3 was also observed in the studied locations. The most prevalent genomes with patterns of variance (confined in a cluster) remain unclassified, and are here proposed as A4-clade based on its divergence within the A cluster. Conclusions: The viral haplotypes may link their persistence to geo-climatic conditions and host response. Multipronged strategies including molecular surveillance based on real-time viral genomic data is of paramount importance for a timely management of the pandemic.

SWI/SNF complex prevents lineage reversion and induces temporal patterning in neural stem cells.

Members of the SWI/SNF chromatin-remodeling complex are among the most frequently mutated genes in human cancer, but how they suppress tumorigenesis is currently unclear. Here, we use Drosophila neuroblasts to demonstrate that the SWI/SNF component Osa (ARID1) prevents tumorigenesis by ensuring correct lineage progression in stem cell lineages. We show that Osa induces a transcriptional program in the transit-amplifying population that initiates temporal patterning, limits self-renewal, and prevents dedifferentiation. We identify the Prdm protein Hamlet as a key component of this program. Hamlet is directly induced by Osa and regulates the progression of progenitors through distinct transcriptional states to limit the number of transit-amplifying divisions. Our data provide a mechanistic explanation for the widespread tumor suppressor activity of SWI/SNF. Because the Hamlet homologs Evi1 and Prdm16 are frequently mutated in cancer, this mechanism could well be conserved in human stem cell lineages. PAPERCLIP:

Neural stem cells in Drosophila: molecular genetic mechanisms underlying normal neural proliferation and abnormal brain tumor formation.

Neural stem cells in Drosophila are currently one of the best model systems for understanding stem cell biology during normal development and during abnormal development of stem cell-derived brain tumors. In Drosophila brain development, the proliferative activity of neural stem cells called neuroblasts gives rise to both the optic lobe and the central brain ganglia, and asymmetric cell divisions are key features of this proliferation. The molecular mechanisms that underlie the asymmetric cell divisions by which these neuroblasts self-renew and generate lineages of differentiating progeny have been studied extensively and involve two major protein complexes, the apical complex which maintains polarity and controls spindle orientation and the basal complex which is comprised of cell fate determinants and their adaptors that are segregated into the differentiating daughter cells during mitosis. Recent molecular genetic work has established Drosophila neuroblasts as a model for neural stem cell-derived tumors in which perturbation of key molecular mechanisms that control neuroblast proliferation and the asymmetric segregation of cell fate determinants lead to brain tumor formation. Identification of novel candidate genes that control neuroblast self-renewal and differentiation as well as functional analysis of these genes in normal and tumorigenic conditions in a tissue-specific manner is now possible through genome-wide transgenic RNAi screens. These cellular and molecular findings in Drosophila are likely to provide valuable genetic links for analyzing mammalian neural stem cells and tumor biology.

Chitosan-based gastroretentive floating drug delivery technology: an updated review.

INTRODUCTION: Gastroretentive floating drug delivery systems have emerged as efficient approaches for enhancing the bioavailability and controlled delivery of various therapeutic agents. Significant advancements exploiting chitosan have been made worldwide, in order to investigate these systems according to patient requirements, both in terms of therapeutic efficacy as well as patient compliance. Such systems precisely control the release rate of the target drug to a specific site, which facilitates an enormous impact on health care. AREAS COVERED: Different novel strategies have been undertaken for the development of various gastric floating dosage forms utilizing chitosan as a promising excipient. The present paper is an earnest attempt to provide new insights on various physicochemical and biological characteristics of chitosan, along with its potential applications in a wide array of biomedical approaches. Numerous and significant research findings in the vistas of chitosan-based gastroretentive floating drug delivery technology are also discussed. EXPERT OPINION: Chitosan has been considered as a unique and efficacious agent possessing a myriad spectrum of desired characteristics. It is emphasized that recent scientific advancements in the use of this excipient as a carrier will yield new generation gastroretentive drug delivery systems, with better pharmacotherapeutic interventions. Further studies are required to unveil the hidden beneficial properties of chitosan and its derivatives, to obtain newer delivery systems which may hold tremendous prospects in the near future.

The parkin mutant phenotype in the fly is largely rescued by metal-responsive transcription factor (MTF-1).

The gene for Parkin, an E3 ubiquitin ligase, is mutated in some familial forms of Parkinson's disease, a severe neurodegenerative disorder. A homozygous mutant of the Drosophila ortholog of human parkin is viable but results in severe motoric impairment including an inability to fly, female and male sterility, and a decreased life span. We show here that a double mutant of the genes for Parkin and the metal-responsive transcription factor 1 (MTF-1) is not viable. MTF-1, which is conserved from insects to mammals, is a key regulator of heavy metal homeostasis and detoxification and plays additional roles in other stress conditions, notably oxidative stress. In contrast to the synthetic lethality of the double mutant, elevated expression of MTF-1 dramatically ameliorates the parkin mutant phenotype, as evidenced by a prolonged life span, motoric improvement including short flight episodes, and female fertility. At the cellular level, muscle and mitochondrial structures are substantially improved. A beneficial effect is also seen with a transgene encoding human MTF-1. We propose that Parkin and MTF-1 provide complementary functions in metal homeostasis, oxidative stress and other cellular stress responses. Our findings also raise the possibility that MTF-1 gene polymorphisms in humans could affect the severity of Parkinson's disease.

Extended lifespan of Drosophila parkin mutants through sequestration of redox-active metals and enhancement of anti-oxidative pathways.

The mechanisms underlying neuron death in Parkinson's disease are unknown, but both genetic defects and environmental factors are implicated in its pathogenesis. Mutations in the parkin gene lead to autosomal recessive juvenile Parkinsonism (AR-JP). Here we report that compared to control flies, Drosophila lacking parkin show significantly reduced lifespan but no difference in dopamine neuron numbers when raised on food supplemented with environmental pesticides or mitochondrial toxins. Moreover, chelation of redox-active metals, anti-oxidants and overexpression of superoxide dismutase 1 all significantly reversed the reduced longevity of parkin-deficient flies. Finally, parkin deficiency exacerbated the rough eye phenotype of Drosophila caused by overexpression of the copper importer B (Ctr1B). Taken together, our results demonstrate an important function of parkin in the protection against redox-active metals and pesticides implicated in the etiology of Parkinson's disease. They also corroborate that oxidative stress, perhaps as a consequence of mitochondrial dysfunction, is a major determinant of morbidity in parkin mutant flies.

Zinc supplement greatly improves the condition of parkin mutant Drosophila.

Parkinson's disease (PD) is a progressive neurodegenerative disorder in which oxidative stress is implicated as a major causative factor. Mutations in the gene encoding Parkin, a ubiquitin ligase, are responsible for a familial form of PD. In a Drosophila disease model lacking Parkin (park(25) null mutant), we tested the effect of zinc supplementation. Zinc is an essential trace metal and a component of many enzymes and transcriptional regulators. Unlike copper and iron, zinc is not redox-active and under most conditions serves as an antioxidant. We find that the condition of parkin mutants raised on zinc-supplemented food is greatly improved. At zinc concentrations where controls begin to show adverse effects as a result of the metal supplement, parkin mutants perform best, as manifested in a higher frequency of reaching adulthood, extended lifespan and improved motoric abilities.