Photocatalytic Proficiency of Cinnoline Moiety for Cross-Coupling Reactions: A Two in One Photocatalyst.

Herein, we have developed a new class of organic photocatalysts that can mimic transition metals for several oxidative and reductive organic cross-coupling transformations. Due to its wide potential window in both the oxidation and reduction ranges, cinnoline exhibits dual catalytic activity under visible light illumination, acting as both a photoreductant and photooxidant.

Introducing Phenalenyl-Based Organic Lewis Acid as a Photocatalyst to Facilitate Oxidative Azolation of Unactivated Arenes.

By revealing the robust photooxidant properties of phenalenyl-based organic Lewis acid, we have introduced this moiety as an effective organophotocatalyst for the oxidative azolation of unactivated and feedstock arenes. In addition to its tolerance for various functional groups and scalability, this photocatalyst was shown to be promising for the defluorinative azolation of fluoroarenes.

Electrochemical Activation of the C-X Bond on Demand: Access to the Atom Economic Group Transfer Reaction Triggered by Noncovalent Interaction.

An atom economic method demonstrates the involvement of noncovalent interaction via hydrogen or halogen bonding interaction in triggering paired electrolysis for the group transfer reactions. Specifically, this method demonstrated the bromination of several aromatic and heteroaromatic compounds through the activation of the C(sp3)-Br bond of organic-bromo derivatives on demand. This electrochemical protocol is mild, and mostly no additional electrolyte is needed, which makes the workup process straightforward. Unlike the existing regioselective monobromination methods, this work utilizes a relatively small amount (1.2 equiv) of bromine surrogates that releases bromine on demand under the electrochemical condition and after completion of the reaction generates acetophenone as a useful byproduct. Green metrics indicate this protocol has a very good atom efficiency with an E-factor of 26.86 kg of waste/1 kg of product. In addition to the scale-up process, this strategy could be extended to the transfer of chlorine and thioaryl units. An extensive mechanistic study is accomplished to validate the hypothesis of noncovalent interaction using computational, spectroscopic, and cyclic voltammetry studies. Finally, the applicability of this newly developed nonbonding interaction to trigger paired electrolysis was extended to the chemoselective debromination of several dihalo organic compounds.

Electricity Induced Rhodium-Catalyzed Oxidative C-H/N-H Annulation of Alkynes with Arylhydrophthalazinediones.

The development of stoichiometric oxidant-free regioselective annulation protocol is a challenging aspect in organic synthesis. Herein, we disclose electricity as a greener oxidant for the C-H/N-H annulation to construct cinnolines using rhodium(III) catalyst under mild conditions. A detailed mechanistic investigation revealed the possibility of both Rh(III/I) and Rh(III/IV) catalytic cycles for the formation of annulated product. Exclusive regioselectivity, diverse substrate scope, and commercially available cheap graphite electrodes are key features of this protocol.

Exploring Eosin Y as a bimodular catalyst: organophotoacid mediated Minisci-type acylation of N-heteroarenes.

Here we report Eosin Y as a bimodular catalyst for Minisci-type acylation reactions. The formation of organic exciplexes between photoexcited Eosin Y and N-heteroarenes was found to be a stabilizing factor for photoacid catalysis under optimized conditions. Spectroscopic investigations such as steady state fluorescence quenching and dynamic lifetime quenching experiments were employed to better understand the role of Eosin Y as both a photoredox catalyst and a photoacid. Feedstock aldehydes were employed as acyl radical precursors for engaging in C-C bond formation reactions with a variety of nitrogen containing heterocycles.

Visible-Light-Mediated Cross Dehydrogenative Coupling of Thiols with Aldehydes: Metal-Free Synthesis of Thioesters at Room Temperature.

Thioesters play a crucial role in biological systems and serve as important building blocks for organic synthesis. Herein, Eosin Y and TBHP mediated photochemical cross dehydrogenative coupling (PCDC) between feedstock aldehydes and thiols has been described at room temperature to synthesize thioesters. This thioesterification protocol proceeds smoothly to give the desired products in good to excellent yields by the suitable PCDC of both alkyl/aryl- aldehydes with a variety of alkyl/aryl-thiols and generates water and tBuOH as green byproducts. This method is also found to be scalable with good efficiency. Mechanistic investigations reveal that under this photochemical condition, the formation of acyl radical can be achieved from aldehyde. This acyl radical was further intercepted with an intermediate disulfide, generated in situ via the dehydrogenation of thiol to give the desired thioester. Moreover, disulfides, which are relatively easier to handle, also provided good to excellent yields in the optimized reaction condition. This protocol was further extended toward the more challenging direct transformation of alcohols to thioesters.

Electrifying Sustainability on Transition Metal-Free Modes: An Eco-Friendly Approach for the Formation of C-N Bonds.

Embracing sustainable green methodologies and techniques in chemical transformations has always been in the limelight to the synthetic community. Electrosynthesis has emerged as a powerful, sustainable synthetic tool for molecular synthesis exploiting inexpensive electricity in place of sacrificial chemical oxidizing/reducing reagents. Herein, recent advances in the incorporation of transition metal-free redox mediators in electrosynthesis for the construction of C-N bonds are outlined. Furthermore, conjugation of this strategy with flow catalysis allows easy scale up of the synthesis of molecular assembly. This comprehensive Review provides an overview of metal-free mediated electro-construction of C-N bonds, focusing on the reaction mechanisms involved and its synthetic applications.

Probing the versatility of metallo-electro hybrid catalysis: enabling access towards facile C-N bond formation.

The development of versatile and mild methodologies for C-N bond construction has always been a hot topic of interest in synthetic organic chemistry. In recent years, electrochemistry has emerged as a promising green and sustainable environmentally benign approach to carry out these transformations under mild conditions utilizing electrons as oxidizing/reducing agents. The current state-of-the-art in combining electrocatalysis with transition metal catalysis has gained significant attention. This hybrid synthetic methodology has increasingly become a common tool and offers many potential advantages compared to direct electrolysis. This review comprehensively highlights recent developments in the merging of transition metal catalysis in electro-organic synthesis for the facile construction of C-N bonds. In this review major emphasis is given to mechanistic investigations and their synthetic applications of this hybrid catalysis.

Infants with Atypical Presentations of Alveolar Capillary Dysplasia with Misalignment of the Pulmonary Veins Who Underwent Bilateral Lung Transplantation.

OBJECTIVE: To describe disease course, histopathology, and outcomes for infants with atypical presentations of alveolar capillary dysplasia with misalignment of the pulmonary veins (ACDMPV) who underwent bilateral lung transplantation. STUDY DESIGN: We reviewed clinical history, diagnostic studies, explant histology, genetic sequence results, and post-transplant course for 6 infants with atypical ACDMPV who underwent bilateral lung transplantation at St. Louis Children's Hospital. We compared their histology with infants with classic ACDMPV and compared their outcomes with infants transplanted for other indications. RESULTS: In contrast with neonates with classic ACDPMV who present with severe hypoxemia and refractory pulmonary hypertension within hours of birth, none of the infants with atypical ACDMPV presented with progressive neonatal respiratory failure. Three infants had mild neonatal respiratory distress and received nasal cannula oxygen. Three other infants had no respiratory symptoms at birth and presented with hypoxemia and pulmonary hypertension at 2-3 months of age. Bilateral lung transplantation was performed at 4-20 months of age. Unlike in classic ACDMPV, histopathologic findings were not distributed uniformly and were not diffuse. Three subjects had apparent nonmosaic genetic defects involving FOXF1. Two infants had extrapulmonary anomalies (posterior urethral valves, inguinal hernia). Three transplanted children are alive at 5-16 years of age, similar to outcomes for infants transplanted for other indications. Lung explants from infants with atypical ACDMPV demonstrated diagnostic but nonuniform histopathologic findings. CONCLUSIONS: The 1- and 5-year survival rates for infants with atypical ACDMPV are similar to infants transplanted for other indications. Given the clinical and histopathologic spectra, ACDMPV should be considered in infants with hypoxemia and pulmonary hypertension, even beyond the newborn period.

Neck blast disease influences grain yield and quality traits of aromatic rice.

A critical investigation was conducted to find out the effect of neck blast disease on yield-contributing characters, and seed quality traits of aromatic rice in Bangladesh. Both healthy and neck-blast-infected panicles of three aromatic rice cultivars (high-yielding and local) were collected and investigated at Plant Pathology Division, Bangladesh Rice Research Institute (BRRI), Gazipur, Bangladesh. All of the tested varieties were highly susceptible to neck blast disease under natural conditions, though no leaf blast symptoms appear on leaves. Neck blast disease increased grain sterility percentages, reduced grain size, yield and quality traits of seeds. The degrees of yield and seed quality reduction depended on disease severity and variety's genetic make-up. Unfilled grains were the main source of seed-borne pathogen, especially for blast in the seed lot. Transmission of blast pathogen from neck (panicle base) to seed was very poor. These findings are important, especially concerning the seed certification programme in which seed lots are certified on the basis of field inspection. Finally, controlled experiments are needed to draw more critical conclusions.

Phenotypic screening and molecular analysis of blast resistance in fragrant rice for marker assisted selection.

Experiments were conducted to identify blast-resistant fragrant genotypes for the development of a durable blast-resistant rice variety during years 2012-2013. The results indicate that out of 140 test materials including 114 fragrant germplasms, 25 differential varieties (DVs) harbouring 23 blast-resistant genes, only 16 fragrant rice germplasms showed comparatively better performance against a virulent isolate of blast disease. The reaction pattern of single-spore isolate of Magnaporthe oryzae to differential varieties showed that Pish, Pi9, Pita-2 and Pita are the effective blast-resistant genes against the tested blast isolates in Bangladesh. The DNA markers profiles of selected 16 rice germplasms indicated that genotype Chinigura contained Pish, Pi9 and Pita genes; on the other hand, both BRRI dhan50 and Bawaibhog contained Pish and Pita genes in their genetic background. Genotypes Jirakatari, BR5, and Gopalbhog possessed Pish gene, while Uknimodhu, Deshikatari, Radhunipagol, Kalijira (3), Chinikanai each contained the Pita gene only. There are some materials that did not contain any target gene(s) in their genetic background, but proved resistant in pathogenicity tests. This information provided valuable genetic information for breeders to develop durable blast-resistant fragrant or aromatic rice varieties in Bangladesh.

Two deletions overlapping a distant FOXF1 enhancer unravel the role of lncRNA LINC01081 in etiology of alveolar capillary dysplasia with misalignment of pulmonary veins.

Position effects due to disruption of distant cis-regulatory regions have been reported for over 40 human gene loci; however, the underlying mechanisms of long-range gene regulation remain largely unknown. We report on two patients with alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) caused by overlapping genomic deletions that included a distant FOXF1 transcriptional enhancer mapping 0.3 Mb upstream to FOXF1 on 16q24.1. In one patient with atypical late-onset ACDMPV, a ∼1.5 Mb deletion removed the proximal 43% of this enhancer, leaving the lung-specific long non-coding RNA (lncRNA) gene LINC01081 intact. In the second patient with severe neonatal-onset ACDMPV, an overlapping ∼194 kb deletion disrupted LINC01081. Both deletions arose de novo on maternal copy of the chromosome 16, supporting the notion that FOXF1 is paternally imprinted in the human lungs. RNAi-mediated knock-down of LINC01081 in normal fetal lung fibroblasts showed that this lncRNA positively regulates FOXF1 transcript level, further indicating that decrease in LINC01081 expression can contribute to development of ACDMPV.

Comparative analyses of lung transcriptomes in patients with alveolar capillary dysplasia with misalignment of pulmonary veins and in foxf1 heterozygous knockout mice.

Alveolar Capillary Dysplasia with Misalignment of Pulmonary Veins (ACDMPV) is a developmental disorder of the lungs, primarily affecting their vasculature. FOXF1 haploinsufficiency due to heterozygous genomic deletions and point mutations have been reported in most patients with ACDMPV. The majority of mice with heterozygous loss-of-function of Foxf1 exhibit neonatal lethality with evidence of pulmonary hemorrhage in some of them. By comparing transcriptomes of human ACDMPV lungs with control lungs using expression arrays, we found that several genes and pathways involved in lung development, angiogenesis, and in pulmonary hypertension development, were deregulated. Similar transcriptional changes were found in lungs of the postnatal day 0.5 Foxf1+/- mice when compared to their wildtype littermate controls; 14 genes, COL15A1, COL18A1, COL6A2, ESM1, FSCN1, GRINA, IGFBP3, IL1B, MALL, NOS3, RASL11B, MATN2, PRKCDBP, and SIRPA, were found common to both ACDMPV and Foxf1 heterozygous lungs. Our results advance knowledge toward understanding of the molecular mechanism of ACDMPV, lung development, and its vasculature pathology. These data may also be useful for understanding etiologies of other lung disorders, e.g. pulmonary hypertension, bronchopulmonary dysplasia, or cancer.

Novel FOXF1 mutations in sporadic and familial cases of alveolar capillary dysplasia with misaligned pulmonary veins imply a role for its DNA binding domain.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare and lethal developmental disorder of the lung defined by a constellation of characteristic histopathological features. Nonpulmonary anomalies involving organs of gastrointestinal, cardiovascular, and genitourinary systems have been identified in approximately 80% of patients with ACD/MPV. We have collected DNA and pathological samples from more than 90 infants with ACD/MPV and their family members. Since the publication of our initial report of four point mutations and 10 deletions, we have identified an additional 38 novel nonsynonymous mutations of FOXF1 (nine nonsense, seven frameshift, one inframe deletion, 20 missense, and one no stop). This report represents an up to date list of all known FOXF1 mutations to the best of our knowledge. Majority of the cases are sporadic. We report four familial cases of which three show maternal inheritance, consistent with paternal imprinting of the gene. Twenty five mutations (60%) are located within the putative DNA-binding domain, indicating its plausible role in FOXF1 function. Five mutations map to the second exon. We identified two additional genic and eight genomic deletions upstream to FOXF1. These results corroborate and extend our previous observations and further establish involvement of FOXF1 in ACD/MPV and lung organogenesis.

A novel mutation in FOXF1 gene associated with alveolar capillary dysplasia with misalignment of pulmonary veins, intestinal malrotation and annular pancreas.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare, fatal, neonatal developmental lung disorder, which usually presents as persistent pulmonary hypertension unresponsive to treatment. The authors report the case of a neonate with persistent pulmonary hypertension, associated with duodenal stenosis secondary to annular pancreas and intestinal malrotation. Support treatment, inhaled nitric oxide, oral sildenafil and nebulized iloprost were used with no clinical improvement. The neonate presented an overwhelming course, with hypoxemia refractory to treatment. At autopsy lung histology showed the characteristic features of ACD/MPV. DNA sequence analysis revealed a heterozygous nonsense mutation c.539C>A;p.S180X, in the first exon of FOXF1. FOXF1 has been identified as one of the genes responsible for ACD/MPV associated with multiple congenital malformations. This clinical case is the first report of a heterozygous nonsense mutation c.539C>A;p.S180X in the first exon of FOXF1, in a patient with ACD/MPV associated with annular pancreas and intestinal malrotation.

'Proptosis'--may be the only presenting feature of small cell lung cancer: a case report.

Orbital metastasis from solid tumours is an uncommon entity and lung, breast and nasopharyngeal cancers are the common sites causing such a metastasis. Proptosis as the only presenting feature without any symptom suggesting lung as the primary site is very rare. Here is a report of a patient who presented with proptosis as the only complaint and subsequent investigations proved it to be due to small cell lung cancer metastasis and without metastatic spread to any other site.

A familial case of alveolar capillary dysplasia with misalignment of pulmonary veins supports paternal imprinting of FOXF1 in human.

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV) is a rare developmental lung disorder that is uniformly lethal. Affected infants die within the first few weeks of their life despite aggressive treatment, although a few cases of late manifestation and longer survival have been reported. We have shown previously that mutations and deletions in FOXF1 are a cause of this disorder. Although most of the cases of ACD/MPV are sporadic, there have been infrequent reports of familial cases. We present a family with five out of six children affected with ACD/MPV. DNA analysis identified a missense mutation (c.416G>T; p.Arg139Leu) in the FOXF1 gene that segregated in the three affected siblings tested. The same variant is also present as a de novo mutation in the mother and arose on her paternally derived chromosome 16. The two tested affected siblings share the same chromosome 16 haplotype inherited from their maternal grandfather. Their single healthy sibling has a different chromosome 16 haplotype inherited from the maternal grandmother. The results are consistent with paternal imprinting of FOXF1 in human.

Small noncoding differentially methylated copy-number variants, including lncRNA genes, cause a lethal lung developmental disorder.

An unanticipated and tremendous amount of the noncoding sequence of the human genome is transcribed. Long noncoding RNAs (lncRNAs) constitute a significant fraction of non-protein-coding transcripts; however, their functions remain enigmatic. We demonstrate that deletions of a small noncoding differentially methylated region at 16q24.1, including lncRNA genes, cause a lethal lung developmental disorder, alveolar capillary dysplasia with misalignment of pulmonary veins (ACD/MPV), with parent-of-origin effects. We identify overlapping deletions 250 kb upstream of FOXF1 in nine patients with ACD/MPV that arose de novo specifically on the maternally inherited chromosome and delete lung-specific lncRNA genes. These deletions define a distant cis-regulatory region that harbors, besides lncRNA genes, also a differentially methylated CpG island, binds GLI2 depending on the methylation status of this CpG island, and physically interacts with and up-regulates the FOXF1 promoter. We suggest that lung-transcribed 16q24.1 lncRNAs may contribute to long-range regulation of FOXF1 by GLI2 and other transcription factors. Perturbation of lncRNA-mediated chromatin interactions may, in general, be responsible for position effect phenomena and potentially cause many disorders of human development.

Primary fallopian tube carcinoma with metastasis in the contralateral ovary.

Primary malignant neoplasm of the fallopian tube is one of the rarest gynaecological malignancies and a pre-operative diagnosis is often missed due to its diagnostic confusion with the tubo-ovarian mass, hydrosalpinx, ectopic pregnancy and ovarian malignancy. Transcoelomic, lymphatic, transluminal and haematogenous spread may occur to the other abdominal and pelvic organs as well as to the distant sites. Though the body of the uterus, ovaries and the contralateral fallopian tube are frequently involved, in the present case the contralateral ovary was the only site of involvement which is very unusual.