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Premise of the Study: The North American Cercis clade spans dry to mesic climates and exhibits complex morphological variation. We tested various proposed species classifications of this group and whether aspects of leaf morphology, particularly the “drip‐tip” in some regional populations, are adaptive and/or linked with phylogeny. Methods: We made measurements on over 1100 herbarium specimens from throughout North America and analyzed the data with univariate and multivariate approaches. We analyzed phylogenetically DNA sequence data from nuclear ITS and three plastid regions from 40 samples, and estimated divergence times with a relaxed‐clock Bayesian analysis. We used climate and geographic position data to predict the variation observed in leaf size and shape by using stepwise multiple linear regressions. Key Results: Morphometric analyses yielded a pattern of continuous and often clinal character variation across North America, without correlated gaps in character states. Conversely, phylogenetic and divergence time analyses yielded distinct clades from California, the interior west, and eastern North America separated by between ~12 and 16 million years. Multiple regressions yielded highly significant correlations between leaf apex shape and precipitation of the warmest quarter. Conclusions: Despite a pattern of continuous morphological character variation, the long period of geographic and presumably genetic isolation warrants the delimitation of three species. Predictive modeling supports the adaptive value of acuminate apices or “drip‐tips” in mesic habitats. This suggests that Cercis leaves change more rapidly than inferred from parsimony reconstruction, which has implications for the evolution of the dry floras of North America and Eurasia. [ABSTRACT FROM AUTHOR]

Aim We sought to reconstruct the historical biogeography of the amphi-Pacific tropical disjunct plant family Symplocaceae in the context of competing Northern Hemisphere (boreotropical) versus Southern Hemisphere (West Gondwanan) hypotheses for its origin and spread. Location Americas, western Pacific Rim, fossil localities in Europe. Methods We derived a dated phylogeny using a relaxed clock on a data set of 114 terminals, four genic regions (three plastid regions and the nuclear ribosomal internal transcribed spacer region) and six fossil calibrations. We inferred ancestral geographical ranges with maximum likelihood under a dispersal-extinction-cladogenesis model, with the probability of dispersal constrained by areal distance and palaeogeography. Results We inferred a Eurasian origin for crown-node Symplocaceae at c. 52 Ma, followed by dispersal to North America (including Mesoamerica) at c. 52-38 Ma. Most of the highest likelihood intra-American dispersals recovered in the analysis trended from north to south, with none from south to north. Six intra-American dispersals were inferred to have originated in North America, with lineages either terminating in the Antilles or migrating to South America at various times. One additional North American lineage emigrated back to Eurasia in the late Miocene. Main conclusions The predominantly southwards American migrations inferred here for the Symplocaceae conform to the boreotropics hypothesis, apparently driven by cooling and drying climates in the later Cenozoic. The inferred Eurasian origin for the family corroborates a more specific European origin, as suggested independently by its fossil fruit record. Of the lineages ultimately arriving in South America from North America, two are inferred to have migrated through the Antilles (by island-hopping) and three through Mesoamerica. The timing of one of the Mesoamerican events, inferred to be between 8.9 and 7.5 Ma, implies over-water dispersal under the prevailing model of Isthmus of Panama formation, but also accords with overland migration under a model of earlier formation. [ABSTRACT FROM AUTHOR]

Symplocos comprises ∼300 species of woody flowering plants with a disjunct distribution between the warm-temperate to tropical regions of eastern Asia and the Americas. Phylogenetic analyses of 111 species of Symplocos based on the nuclear ribosomal internal transcribed spacer (ITS) region and the chloroplast genes rpl16, marK, and trnL-trnF yielded topologies in which only one of the four traditionally recognized subgenera (Epigenia; Neotropics) is monophyletic. Section Cordyloblaste (subgenus Symplocos; eastern Asia) is monophyletic and sister to a group comprising all other samples of Symplocos. Section Palura (subgenus Hopea; eastern Asia) is sister to a group comprising all other samples of Symplocos except those of section Cordyloblaste. Symplocos wikstroemiifolia (eastern Asia) and S. tinctoria (southeastern United States), both of subgenus Hopea, form a clade that groups with S. longipes (tropical North America) and the species of subgenus Epigenia. The remaining samples of subgenus Hopea (eastern Asia) form a clade. Section Neosymplocos (subgenus Microsymplocos; Neotropics) is well nested within a clade otherwise comprising the samples of section Symplocastrum (subgenus Symplocos; Neotropics). Section Urbaniocharis (subgenus Microsymplocos; Antilles) groups as sister to the clade comprising Symplocastrum and Neosymplocos. The data support the independent evolution of deciduousness among section Palura and S. tinctoria. The early initial divergence of sections Cordyloblaste and Palura from the main group warrants their recognition at taxonomic levels higher than those at which they are currently placed. An inferred eastern Asian origin for Symplocos with subsequent dispersal to the Americas is consistent with patterns from other phylogenetic studies of eastern Asian-American disjunct plant groups but contrary to a North American origin inferred from the earliest fossil occurrences of the genus. [ABSTRACT FROM AUTHOR]

The members of tribe Microlicieae in the flowering plant family Melastomataceae are nearly all endemic to the cerrado biome of Brazil. Traditional classifications of the Melastomataceae have attributed between 15 and 17 genera to the Microticieae, but subsequent revisions have circumscribed the tribe more narrowly. The monophyly and intergeneric relationships of the Microlicieae were evaluated through phylogenetic analyses with molecular and morphological data sets. Incorporation of DNA sequences from the intron of the chloroplast gene rpl16 into a previously generated family-wide data set yielded a clade comprising Chaetostoma, Lavoisiera, Microlicia, Rhynchanthera, Stenodon, and Trembleya ("core Microlicieae"), with Rhynchanthera as the first-diverging lineage. The other four genera of Microlicieae sampled are placed in other clades: Eriocnema with Miconieae; Siphanthera with Aciotis, Nepsera, and Acisanthera of Melastomeae; Castratella as sister to Monochaetum of Melastomeae; and Cambessedesia as part of an unresolved polytomy in a large clade that includes most Melastomataceae. Analyses of the chloroplast genes rbcL and ndhF that included three core genera produced similar results, as did the combined analysis of all three data sets. Combined parsimony analyses of DNA sequences from rpl16 and the nuclear ribosomal intercistronic transcribed spacer (ITS) region of 22 species of core Microlicieae yielded generally low internal support values. Lavoisiera, recently redefined on the basis of several morphological characters, was strongly supported as monophyletic. A morphological phylogenetic analysis of the Microlicieae based on 10 parsimony-informative characters recovered a monophyletic core Microlicieae but provided no further resolution among genera. Penalized likelihood analysis with two calibration time windows produced an age estimate of 3.7 million years for the time of initial divergence of strictly Brazilian core Microlicieae. This date is in general agreement with the estimated age of the most active stage of development of cerrado vegetation and implies an adaptive shift from hydric to seasonally dry habitats during the early evolution of this group. [ABSTRACT FROM AUTHOR]

Abstract Genetic deficiency of monoamine oxidase-A (MAO-A) induces major alterations of mood and behaviour in human. Because serotonin (5-HT) is involved in mood regulation, and MAO-A is responsible for the catabolism of 5-HT, we investigated 5-HT mechanisms in knock-out mice (2-month-old) lacking MAO-A, using microdialysis, electrophysiological, autoradiographic and molecular biology approaches. Compared to paired wild-type mice, basal extracellular 5-HT levels were increased in ventral hippocampus (+202%), frontal cortex (+96%) and dorsal raphe nucleus (DRN, +147%) of MAO-A mutant mice. Conversely, spontaneous firing rate of 5-HT neurons in the DRN (recorded under chloral hydrate anaesthesia) was ∼40% lower in mutants. Acute 5-HT reuptake blockade by citalopram (0.2 and 0.8 mg/kg i.v.) produced a much larger increase in extracellular 5-HT levels (by ∼4 fold) and decrease in DRN neuronal firing (with a ∼4.5 fold decrease in the drug's ED50 ) in MAO-A knock-out mice, which expressed lower levels of the 5-HT transporter throughout the brain (-13 to -34% compared to wild-type levels). The potency of the 5-HT1A agonist 8-OH-DPAT to produce hypothermia and to reduce the firing of DRN serotoninergic neurons was significantly less in the mutants, indicating a desensitization of 5-HT1A autoreceptors. This was associated with a decreased autoradiographic labelling of these receptors (-27%) in the DRN. Altogether, these data indicate that, in MAO-A knock-out mice, the enhancement of extracellular 5-HT levels induces a down-regulation of the 5-HT transporter, and a desensitization of 5-HT1A autoreceptors which allows the maintenance of tonic activity of 5-HT neurons in the DRN. [ABSTRACT FROM AUTHOR]

Shwachman-Diamond syndrome (SDS) is characterized by neutropenia, exocrine pancreatic insufficiency and skeletal abnormalities. SDS bone marrow haematopoietic progenitors show increased apoptosis and impairment in granulocytic differentiation. Loss of Shwachman-Bodian-Diamond syndrome (SBDS) expression results in reduced eukaryotic 80S ribosome maturation. Biallelic mutations in the SBDS gene are found in ~90% of SDS patients, ~55% of whom carry the c.183-184TA>CT nonsense mutation. Several translational readthrough-inducing drugs aimed at suppressing nonsense mutations have been developed. One of these, ataluren, has received approval in Europe for the treatment of Duchenne muscular dystrophy. We previously showed that ataluren can restore full-length SBDS protein synthesis in SDS-derived bone marrow cells. Here, we extend our preclinical study to assess the functional restoration of SBDS capabilities in vitro and ex vivo. Ataluren improved 80S ribosome assembly and total protein synthesis in SDS-derived cells, restored myelopoiesis in myeloid progenitors, improved neutrophil chemotaxis in vitro and reduced neutrophil dysplastic markers ex vivo. Ataluren also restored full-length SBDS synthesis in primary osteoblasts, suggesting that its beneficial role may go beyond the myeloid compartment. Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation., (© 2023 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

Eating disorders and substance use disorders frequently co-occur. Twin studies reveal shared genetic variance between liabilities to eating disorders and substance use, with the strongest associations between symptoms of bulimia nervosa and problem alcohol use (genetic correlation [r g ], twin-based = 0.23-0.53). We estimated the genetic correlation between eating disorder and substance use and disorder phenotypes using data from genome-wide association studies (GWAS). Four eating disorder phenotypes (anorexia nervosa [AN], AN with binge eating, AN without binge eating, and a bulimia nervosa factor score), and eight substance-use-related phenotypes (drinks per week, alcohol use disorder [AUD], smoking initiation, current smoking, cigarettes per day, nicotine dependence, cannabis initiation, and cannabis use disorder) from eight studies were included. Significant genetic correlations were adjusted for variants associated with major depressive disorder and schizophrenia. Total study sample sizes per phenotype ranged from ~2400 to ~537 000 individuals. We used linkage disequilibrium score regression to calculate single nucleotide polymorphism-based genetic correlations between eating disorder- and substance-use-related phenotypes. Significant positive genetic associations emerged between AUD and AN (r g = 0.18; false discovery rate q = 0.0006), cannabis initiation and AN (r g = 0.23; q < 0.0001), and cannabis initiation and AN with binge eating (r g = 0.27; q = 0.0016). Conversely, significant negative genetic correlations were observed between three nondiagnostic smoking phenotypes (smoking initiation, current smoking, and cigarettes per day) and AN without binge eating (r gs = -0.19 to -0.23; qs < 0.04). The genetic correlation between AUD and AN was no longer significant after co-varying for major depressive disorder loci. The patterns of association between eating disorder- and substance-use-related phenotypes highlights the potentially complex and substance-specific relationships among these behaviors., (© 2020 Society for the Study of Addiction.)

Discrepancies in the role of the 40 bp VNTR polymorphism of the dopamine transporter gene (DAT1) in attention-deficit hyperactivity disorder (ADHD) could be due to various sources of genetic or phenotypical heterogeneity. We therefore analyzed a sample of 146 ADHD children and their parents, with a transmission disequilibrium test (TDT) design, assessing age, inattention, and hyperactivity dimensions and total score of the ADHD Rating Scale, the number of errors and the total score at Stroop Color-Word test, and the total score at the Trail Making Test. The TDT for 10-repeat (10-R) allele shows a perfect lack of transmission bias (Mc Nemar chi(2) = 0) and PBAT analyses showed no role of this polymorphism for any of the studied endophenotypes. Lack of statistical power is always a possibility, but with a sample size above the average of the majority of previous studies, and an odds ratio (number of transmitted versus untransmitted 10-R allele) of 1.00 exactly, this possibility may be considered as not very likely., (Copyright 2008 Wiley-Liss, Inc.)

Pharmacogenetic studies investigating the 40-bp VNTR polymorphism at SLC6A3 and methylphenidate response have shown conflicting results and large differences in study design and efficacy endpoints. Our objective was to investigate the relation between the 3'-VNTR at SLC6A3 and variability in methylphenidate response in a sample of 141 ADHD children and adolescents, assessed before and after methylphenidate treatment with both clinical and neuropsychological outcome measures. 10-R homozygotes were significantly overrepresented in the low response group, but no genotype effect was shown in cognitive variables improvement. A meta-analysis of pharmacogenetic studies with comparable data (responders vs. non-responders) on a total of 475 subjects showed a significant association between the 10-10 genotype and low rates of methylphenidate response (mean Odds Ratio = 0.46; 95% CI [0.28-0.76]). Heterogeneity between these studies did not reach a significant level but, as publications with different endpoints were excluded from this meta-analysis, our results do not rule out a possible influence of study design., (Copyright 2008 Wiley-Liss, Inc.)

Background: Some studies have reported that the A9 allele of the variable nucleotide tandem repeat (VNTR) of the gene which encodes the dopamine transporter (DAT1/SLC6A3) is associated with alcoholism withdrawal symptoms such as alcohol withdrawal seizures (WSs), whereas others did not. We investigated whether polymorphisms within the DAT1 gene are associated with WS taking into account some of the confounding factors such as the severity of alcohol dependence., Methods: To further assess the role of this gene in WS, we genotyped the VNTR and 7 single nucleotide polymorphisms (SNPs) encompassing the DAT1 gene in a sample of 250 alcohol-dependent subjects (175 men and 75 women), of whom 24% exhibited WSs, taking into account the severity of alcohol dependence., Results: The VNTR is associated with an increased risk of WSs (odd ratio = 3.5; p = 0.019), even when controlling for confounding factors (p = 0.031). As 2 SNPs, in roughly the same location of the gene (namely rs27072 and rs27048), are also associated with WSs, it is possible that the initial association of the VNTR polymorphism was tagging a specific haplotype of this gene. Indeed, in our sample of alcohol-dependent patients, 2 haplotypes were associated with a significantly different risk of WSs., Conclusions: The present study adds evidence for a significant role of the 3' part of the DAT1 gene in WS of alcohol-dependent patients, not only because it is in accordance with previous work, but also because of larger statistical power (as relying on a sample over sampled with the studied phenotype), as it gives a more precise analysis of different SNPs within the DAT1 gene, and as it confirms the association when major potentially confounding factors are taken into account in a logistical regression analysis.