Hydroxymethylation hydroxylation of 1,3-diarylpropene through a catalytic diastereoselective Prins reaction: cyclization logic and access to brazilin core.

A catalytic diastereoselective Prins reaction for hydroxymethylation and hydroxylation of 1,3-diarylpropene was successfully utilized to prepare various 1,3-dioxanes 7 in 14-88% yields. Take advantage of the synthetic intermediate 7h, the key B/C rings in brazilin core could be constructed by the sequential of Friedel-Crafts/Ullmann-Ma rather than Ullmann-Ma/Friedel-Crafts reactions.

Clinical significance and prospective mechanism of increased CDKN2A expression in small cell lung cancer.

BACKGROUND: Although it has been shown that cyclin dependent kinase inhibitor 2A (CDKN2A) plays a significant role in a number of malignancies, its clinicopathological value and function in small cell lung cancer (SCLC) is unclear and warrants additional research. METHODS: The clinical significance of CDKN2A expression in SCLC was examined by multiple methods, including comprehensive integration of mRNA level by high throughput data, Kaplan-Meier survival analysis for prognostic value, and validation of its protein expression using in-house immunohistochemistry. RESULTS: The expression of CDKN2A mRNA in 357 cases of SCLC was evidently higher than that in the control group (n = 525) combing the data from 20 research centers worldwide. The standardized mean difference (SMD) was 3.07, and the area under the curve (AUC) of summary receiver operating characteristic curve (sROC) was 0.97 for the overexpression of CDKN2A. ACC, COAD, KICH, KIRC, PCPG, PRAD, UCEC, UVM patients with higher CDKN2A expression had considerably worse overall survival rates than those with lower CDKN2A expression with the hazard ratio (HR) > 1. CONCLUSION: CDKN2A upregulation extensively enhances the carcinogenesis and progression of SCLC.

A novel SYNJ1 homozygous variant causing developmental and epileptic encephalopathy in an Afro-Caribbean individual.

BACKGROUND: SYNJ1 encodes Synaptojanin-1, a dual-function poly-phosphoinositide phosphatase that is expressed in the brain to regulate neuronal synaptic vesicle dynamics. Biallelic SYNJ1 variants cause a spectrum of clinical manifestations, from early onset parkinsonism to developmental and epileptic encephalopathy. METHODS: Proband-only exome sequencing was used to identify a homozygous SYNJ1 pathogenic variant in an individual with epileptic encephalopathy. Sanger sequencing was used to confirm the variant. RESULTS: We present an Afro-Caribbean female who developed uncontrollable seizures shortly after birth, accompanied by developmental delay and severe generalized dystonia. She had homozygosity for a novel c.242-2A > G variant in SYNJ1 with both parents being heterozygous carriers. An older sister was reported to have had a similar presentation but was not examined. Both siblings died at an approximate age of 16 years. CONCLUSIONS: We report a novel pathogenic variant in SYNJ1 present in homozygosity leading to developmental and epileptic encephalopathy. Currently, there are only 4 reports describing 10 individuals with SYNJ1-related developmental and epileptic encephalopathy. This case expands the clinical knowledge and the allelic heterogeneity associated with SYNJ1 variants.

Contribution of Mendelian Disorders in a Population-Based Pediatric Neurodegeneration Cohort.

OBJECTIVE: To evaluate Mendelian causes of neurodegenerative disorders in a cohort of pediatric patients. STUDY DESIGN: Patients enrolled in the Center for Applied Genomics Biobank at the Children's Hospital of Philadelphia with neurodegenerative symptoms were identified using an algorithm that consisted of including and excluding selected International Classification of Diseases, 9th and 10th edition codes. A manual chart review was then performed to abstract detailed clinical information. RESULTS: Of approximately 100 000 patients enrolled in the Center for Applied Genomics Biobank, 76 had a neurodegenerative phenotype. After chart review, 7 patients were excluded. Of the remaining 69 patients, 42 had a genetic diagnosis (60.9%) and 27 were undiagnosed (39.1%). There were 32 unique disorders. Common diagnoses included Rett syndrome, mitochondrial disorders, and neuronal ceroid lipofuscinoses. CONCLUSIONS: The disorders encountered in our cohort demonstrate the diverse diseases and pathophysiology that contribute to pediatric neurodegeneration. Establishing a diagnosis often informed clinical management, although curative treatment options are lacking. Many patients who underwent genetic evaluation remained undiagnosed, highlighting the importance of continued research efforts in this field.

Expanding the phenotypic spectrum of ARCN1-related syndrome.

PURPOSE: This study aimed to describe the phenotypic and molecular characteristics of ARCN1-related syndrome. METHODS: Patients with ARCN1 variants were identified, and clinician researchers were connected using GeneMatcher and physician referrals. Clinical histories were collected from each patient. RESULTS: In total, we identified 14 cases of ARCN1-related syndrome, (9 pediatrics, and 5 fetal cases from 3 families). The clinical features these newly identified cases were compared to 6 previously reported cases for a total of 20 cases. Intrauterine growth restriction, micrognathia, and short stature were present in all patients. Other common features included prematurity (11/15, 73.3%), developmental delay (10/14, 71.4%), genitourinary malformations in males (6/8, 75%), and microcephaly (12/15, 80%). Novel features of ARCN1-related syndrome included transient liver dysfunction and specific glycosylation abnormalities during illness, giant cell hepatitis, hepatoblastoma, cataracts, and lethal skeletal manifestations. Developmental delay was seen in 73% of patients, but only 3 patients had intellectual disability, which is less common than previously reported. CONCLUSION: ARCN1-related syndrome presents with a wide clinical spectrum ranging from a severe embryonic lethal syndrome to a mild syndrome with intrauterine growth restriction, micrognathia, and short stature without intellectual disability. Patients with ARCN1-related syndrome should be monitored for liver dysfunction during illness, cataracts, and hepatoblastoma. Additional research to further define the phenotypic spectrum and possible genotype-phenotype correlations are required.

A novel unbalanced translocation between chromosomes 5p and 18q leading to dysmorphology and global developmental delay.

BACKGROUND: Individuals with various sized terminal duplications of chromosome 5p or terminal deletions of chromosome 18q have been described. These aberrations may cause congenital malformations and intellectual disability of varying severity. METHODS: Via an international collaborative effort, we obtained a cytogenetic diagnosis for a 5-year-old boy of Afro-Caribbean ancestry who has global developmental delay, dysmorphology, hypotonia, feeding difficulties, bilateral club feet, and intellectual disability. RESULTS: Conventional G-banded karyotyping showed additional chromatin of unknown origin on the long arm of chromosome 18. SNP microarray confirmed the loss of ~6.4 Mb from chromosome 18q: arr[hg19] 18q22.3-q23(71,518,518-77,943,115)x1. The source of the additional chromatin was determined from the microarray to be ~32 Mb from the short arm of chromosome 5 (arr[hg19] 5p13.3-p15.33(51,045-32,062,984)x3). The unbalanced translocation was verified by fluorescent in situ hybridization (FISH). Both parents are healthy and have normal karyotypes suggesting that this abnormality arose de novo in the proband, although gonadal mosaicism in a parent cannot be excluded. CONCLUSION: The combination of clinical features in this individual is most likely due to the partial deletion of 18q and partial duplication of 5p, which to our knowledge has not been previously described.

Experiences with offering pro bono medical genetics services in the West Indies: Benefits to patients, physicians, and the community.

We describe our experiences with organizing pro bono medical genetics and neurology outreach programs on several different resource-limited islands in the West Indies. Due to geographic isolation, small population sizes, and socioeconomic disparities, most Caribbean islands lack medical services for managing, diagnosing, and counseling individuals with genetic disorders. From 2015 to 2019, we organized 2-3 clinics per year on various islands in the Caribbean. We also organized a week-long clinic to provide evaluations for children suspected of having autism spectrum disorder. Consultations for over 100 different individuals with suspected genetic disorders were performed in clinics or during home visits following referral by locally registered physicians. When possible, follow-up visits were attempted. When available and appropriate, clinical samples were shipped to collaborating laboratories for molecular analysis. Laboratory tests included karyotyping, cytogenomic microarray analysis, exome sequencing, triplet repeat expansion testing, blood amino acid level determination, biochemical assaying, and metabolomic profiling. We believe that significant contributions to healthcare by genetics professionals can be made even if availability is limited. Visiting geneticists may help by providing continuing medical education seminars. Clinical teaching rounds help to inform local physicians regarding the management of genetic disorders with the aim of generating awareness of genetic conditions. Even when only periodically available, a visiting geneticist may benefit affected individuals, their families, their local physicians, and the community at large.

Outcomes of surgical patch angioplasty of the coronary artery for diffuse coronary artery disease

Abstract Introduction: Diffuse coronary artery disease (CAD) has a poor prognosis and many patients are ineligible for conventional coronary artery bypass grafting (CABG). This study evaluated the 12-month outcomes of coronary artery reconstruction and surgical patch angioplasty of the coronary artery for diffuse CAD. Methods: A retrospective cohort study of patients who underwent CABG with surgical patch angioplasty of the coronary artery (reconstruction group) or standard CABG alone (standard group) at the Cardiovascular Surgery Department of the local Hospital between January 2014 and January 2016. Follow-up was censored at 12 months after surgery. Results: Cardiopulmonary bypass and aortic cross-clamping durations were longer in the reconstruction group (n=32) than in the standard group (n=125) (P<0.05). There were no differences in graft blood flow and postoperative levels of cardiac markers between the two groups (P>0.05). In the reconstruction group, one patient died; a vein graft showed occlusion. In the standard group, two patients died; one left internal mammary artery graft and three vein grafts showed occlusion. There were no significant differences in mortality, major adverse cardiovascular and cerebrovascular events, and patency between the two groups (P>0.05). Conclusion: Coronary artery reconstruction and surgical patch angioplasty of the coronary artery can be performed for diffuse CAD. Patient outcomes were not significantly different from those of patients who underwent standard CABG.

A homozygous truncating NALCN variant in two Afro-Caribbean siblings with hypotonia and dolichocephaly.

NALCN encodes a sodium ion leak channel expressed in the nervous system that conducts a persistent influx of sodium ions to facilitate action potential formation. Homozygous or compound heterozygous loss of function variants in NALCN cause infantile hypotonia with psychomotor retardation and characteristic facies-1 (IHPRF1; OMIM 615419). Through exome and Sanger sequencing, we found two siblings of Afro-Caribbean ancestry who are homozygous for a known NALCN pathogenic variant, p.Arg735Ter, leading to failure to thrive, severe hypotonia, and dolichocephaly. The older sibling died suddenly without a known etiology after evaluation but before molecular diagnosis. An international collaboration originating from a resource limited Caribbean island facilitated molecular diagnosis. Due to its small population, geographical isolation, and low socioeconomic status, the island lacks many specialty medical services, including clinical genetics. Descriptions of genetic disorders affecting individuals of Afro-Caribbean ancestry are rarely reported in the medical literature. Diagnosis of IHPRF1 is important, as individuals with biallelic pathogenic NALCN variants are severely affected and potentially are at risk for cardiorespiratory arrest. Additionally, knowing the pathogenic variants allows the possibility of prenatal or preimplantation genetic diagnosis.

Application of exome sequencing to diagnose a novel presentation of the Cornelia de Lange syndrome in an Afro-Caribbean family.

BACKGROUND: Cornelia de Lange syndrome (CdLS) comprises a recognizable pattern of multiple congenital anomalies caused by variants of the DNA cohesion complex. Affected individuals may display a wide range of phenotypic severity, even within the same family. METHODS: Exome sequencing and confirmatory Sanger sequencing showed the same previously described p.Arg629Ter NIPBL variant in two half-brothers affected with CdLS. Clinical evaluations were obtained in a pro bono genetics clinic. RESULTS: One brother had relatively mild proportionate limb shortening; the other had complete bilateral hypogenesis of the upper arm with absence of lower arm structures, terminal transverse defects, and no digit remnants. His complex lower limb presentation included long bone deficiency and a deviated left foot. The mother had intellectual disability and microcephaly but lacked facial features diagnostic of the CdLS. CONCLUSION: We describe a collaboration between a pediatrics team from a resource-limited nation and USA-based medical geneticists. Reports describing individuals of West Indian ancestry are rarely found in the medical literature. Here, we present a family of Afro-Caribbean ancestry with CdLS presenting with phenotypic variability, including unusual lower limb abnormalities. The observation of this novel family adds to our knowledge of the phenotypic and molecular aspects of CdLS.

Intragenic Deletions of GNAS in Pseudohypoparathyroidism Type 1A Identify a New Region Affecting Methylation of Exon A/B.

CONTEXT: Pseudohypoparathyroidism type 1A (PHP1A) and pseudopseudohypoparathyroidism (PPHP) are caused by inactivating mutations in the exons of GNAS that encode the alpha-subunit of the stimulatory G protein (Gsα). In some cases abnormal methylation of exon A/B of GNAS, a hallmark of PHP1B, has been reported. OBJECTIVE: To identify the underlying genetic basis for PHP1A/PPHP in patients in whom molecular defects were not detected by GNAS sequencing and microarray-based analysis of copy number variations. METHODS: Whole genome sequencing (WGS) and pyrosequencing of differentially methylated regions (DMRs) of GNAS using genomic deoxyribonucleic acid from affected patients. RESULTS: We identified 2 novel heterozygous GNAS deletions: a 6.4 kb deletion that includes exon 2 of GNAS in the first proband that was associated with normal methylation (57%) of exon A/B DMR, and a 1438 bp deletion in a second PHP1A patient that encompasses the promoter region and 5' untranslated region of Gsα transcripts, which was inherited from his mother with PPHP. This deletion was associated with reduced methylation (32%) of exon A/B DMR. CONCLUSIONS: WGS can detect exonic and intronic mutations, including deletions that are too small to be identified by microarray analysis, and therefore is more sensitive than other techniques for molecular analysis of PHP1A/PPHP. One of the deletions we identified led to reduced methylation of exon A/B DMR, further refining a region needed for normal imprinting of this DMR. We propose that deletion of this region can explain why some PHP1A patients have reduced of methylation of the exon A/B DMR.

Computed tomography shows high fracture prevalence among physically active forager-horticulturalists with high fertility.

Modern humans have more fragile skeletons than other hominins, which may result from physical inactivity. Here, we test whether reproductive effort also compromises bone strength, by measuring using computed tomography thoracic vertebral bone mineral density (BMD) and fracture prevalence among physically active Tsimane forager-horticulturalists. Earlier onset of reproduction and shorter interbirth intervals are associated with reduced BMD for women. Tsimane BMD is lower versus Americans, but only for women, contrary to simple predictions relying on inactivity to explain skeletal fragility. Minimal BMD differences exist between Tsimane and American men, suggesting that systemic factors other than fertility (e.g. diet) do not easily explain Tsimane women's lower BMD. Tsimane fracture prevalence is also higher versus Americans. Lower BMD increases Tsimane fracture risk, but only for women, suggesting a role of weak bone in women's fracture etiology. Our results highlight the role of sex-specific mechanisms underlying skeletal fragility that operate long before menopause.

Bi-Microporous Metal-Organic Frameworks with Cubane [M4 (OH)4 ] (M=Ni, Co) Clusters and Pore-Space Partition for Electrocatalytic Methanol Oxidation Reaction.

Embedding cubane [M4 (OH)4 ] (M=Ni, Co) clusters within the matrix of metal-organic frameworks (MOFs) is a strategy to develop materials with unprecedented synergistic properties. Herein, a new material type based on the pore-space partition of the cubic primitive minimal-surface net (MOF-14-type) has been realized. CTGU-15 made from the [Ni4 (OH)4 ] cluster not only has very high BET surface area (3537 m2 g-1 ), but also exhibits bi-microporous features with well-defined micropores at 0.86 nm and 1.51 nm. Furthermore, CTGU-15 is stable even under high pH (0.1 m KOH), making it well suited for methanol oxidation in basic medium. The optimal hybrid catalyst KB&CTGU-15 (1:2) made from ketjen black (KB) and CTGU-15 exhibits an outstanding performance with a high mass specific peak current of 527 mA mg-1 and excellent peak current density (29.8 mA cm-2 ) at low potential (0.6 V). The isostructural cobalt structure (CTGU-16) has also been synthesized, further expanding the application potential of this material type.

Heterozygous Deletion Impacting SMARCAD1 in the Original Kindred with Absent Dermatoglyphs and Associated Features (Baird, 1964).

In 1964, Baird described a family with adermatoglyphia, facial milia, and skin fragility. Using whole exome sequencing, genotyping, and Sanger sequencing, we identified a 116-kb heterozygous deletion involving exons 1-9 of SMARCAD1 in descendants of this kindred. This contrasts with point mutations within exon 9 in all other reported families.

The open-cubane oxo-oxyl coupling mechanism dominates photosynthetic oxygen evolution: a comprehensive DFT investigation on O-O bond formation in the S4 state.

The dioxygen formation mechanism of biological water oxidation in nature has long been the focus of argument; many diverse mechanistic hypotheses have been proposed. Based on a recent breakthrough in the resolution of the electronic and structural properties of the oxygen-evolving complex in the S3 state, our density functional theory (DFT) calculations reveal that the open-cubane oxo-oxyl coupling mechanism, whose substrates preferably originate from W2 and O5 in the S2 state, emerges as the best candidate for O-O bond formation in the S4 state. This is justified by the overwhelming energetic superiority of this mechanism over alternative mechanisms in both the isomeric open and closed-cubane forms of the Mn4CaO5 cluster; spin-dependent reactivity rooted in variable magnetic couplings was found to play an essential role. Importantly, this oxygen evolution mechanism is supported by the recent discovery of femtosecond X-ray free electron lasers (XFEL), and the origin of the observed structural changes from the S1 to S3 state has been analyzed. In this view, we corroborate the proposed water binding mechanism during S2-S3 transition and correlate the theoretical models with experimental findings from aspects of substrate selectivity according to water exchange kinetics. This theoretical consequence for native metalloenzymes may serve as a significant guide for improving the design and synthesis of biomimetic materials in the field of photocatalytic water splitting.

Draft Genome Sequence of Staphylococcus succinus subsp. succinus Type Strain DSM 14617, Isolated from Plant and Soil Inclusions within 25- to 35-Million-Year-Old Dominican Amber.

Staphylococcus succinus subsp. succinus type strain DSM 14617 was isolated from plant and soil inclusions within 25- to 35-million-year-old Dominican amber. The complete genome sequence of strain DSM 14617T includes a genome of 2.88 Mb (32.94% G+C content) without any plasmids.

Preparation and characterization of Nano-graphite/TiO2 composite photoelectrode for photoelectrocatalytic degradation of hazardous pollutant.

Nano-graphite(Nano-G)/TiO2 composite photoelectrode was fabricated via sol-gel reaction, followed by the hot-press approach. The morphology, structure and light absorption capability of composite was characterized by various characterizations. The photoelectrochemical property and photoelectrocatalytic(PEC) activity of photoelectrode were also investigated. Results revealed that anatase TiO2 nanoparticles with an average diameter of 10nm were dispersed uniformly on the thickness of 2-3nm Nano-G, and TiOC bond was formed. The absorption edge of Nano-G/TiO2 photoelectrode was red-shifted towards low energy region and the enhanced visible light absorption was obtained. The charge transfer resistance of Nano-G/TiO2 photoelectrode was significantly decreased after the addition of Nano-G. And its transient photoinduced current was 10.5 times the value achieved using TiO2 electrode. Nano-G/TiO2 photoelectrode displayed greatly enhanced PEC activity of 99.2% towards the degradation of phenol, which was much higher than the 29.1% and 58.3% degradation seen on TiO2 and Nano-G electrode, respectively. The highly efficient and stable PEC activity of Nano-G/TiO2 photoelectrode was attributed to the synergy effect between photocatalysis and electrocatalysis, as well as enhanced light absorption ability and higher separation efficiency of photogenerated charge carriers. Moreover, contribution of series of reactive species to the PEC degradation of Nano-G/TiO2 photoelectrode was determined.

Compensatory sweating after restricting or lowering the level of sympathectomy: a systematic review and meta-analysis.

OBJECTIVE: To compare compensatory sweating after lowering or restricting the level of sympathectomy. METHOD: A systematic review and meta-analysis were conducted of all randomized controlled trials published in English that compared compensatory sweating after lowering or restricting the level of sympathectomy. The Cochrane collaboration tool was used to assess the risk of bias, and the Mantel-Haenszel odds ratio method was used for the meta-analysis. RESULTS: A total of 11 randomized controlled trials were included, including a total of 1079 patients. Five of the randomized controlled trials studied restricting the level of sympathectomy, and the remaining six studied lowering the level of sympathectomy. CONCLUSIONS: The compiled randomized controlled trial results published so far in the literature do not support the claims that lowering or restricting the level of sympathetic ablation results in less compensatory sweating.

Bisabolane Sesquiterpenoids from the Plant Endophytic Fungus Paraconiothyrium brasiliense.

Brasilamides E-J (1-6), the bisabolane sesquiterpenoids with the 3-cyclohexylfuran (1 and 2) and 3-cyclohexylfuranone (3-6) skeletons, were isolated from the scale-up fermentation cultures of the plant endophytic fungus Paraconiothynium brasiliense Verkley. Although brasilamide E (1) is a known metabolite, its structure elucidation has yet to be described. The structures of 1-6 were elucidated primarily by NMR experiments. Compounds 3-6 were found to be racemic, and 3 was further separated into enantiomers 3a and 3b on a chiral HPLC column. The absolute configurations of 3a and 3b were assigned by electronic circular dichroism calculations. Compound 1 selectively inhibited the proliferation of the breast (MCF-7) and gastric (MGC) cancer cell lines, with IC50 values of 8.4 and 14.7 µM, respectively. Initial mechanistic investigation revealed that compound 1 inhibited the expression of a key energy metabolic enzyme, hexokinase II (HK2), in MCF-7 cells, which resulted in dysfunction of glucose metabolism and ATP depletion and eventually inhibited the proliferation of the breast cancer cells.