bluuebunny/crossref_metadata_2025 huggingface dataset:
Echocardiography from a transhepatic approach in left ventricular assist device patients with difficult transthoracic imaging
Authors: Strachinaru Mihai , Hirsch Alexander , Bowen Daniel , Caliskan Kadir
Published: April 2021

Background

Left ventricular assist devices (LVADs) are increasingly used in the treatment of end-stage heart failure. One important limitation in the follow-up of these patients is the very difficult echocardiographic image, because of the interposition of implanted materials.

Case summary 

We present here a case series of LVAD patients with severely limited transthoracic echocardiographic windows in whom the echocardiographic analysis of the left and right ventricular function could be obtained from a very unusual approach, using a right intercostal transhepatic window, allowing visualization of the heart chambers and quantification of function even in these very challenging cases. In one case, the result was confirmed by computed tomography. In the second case, computed tomography images were unreliable because of strong artefacts from the LVAD system and implantable cardioverter-defibrillator leads, but the transhepatic approach still provided sufficient image quality in order to allow the imaging follow-up of the patient. In the third case, the transhepatic window was the only approach that provided echocardiographic images, and due to the good visualization of the heart cavities, this imaging technique was considered sufficient for follow-up studies in this stable subject with LVAD as destination therapy.

Discussion 

The transhepatic window may represent a good alternative in selected LVAD patients with very difficult acoustic access in traditional transthoracic views. Modified or alternate echocardiographic windows may reduce the need for invasive procedures (transoesophageal echocardiography) or imaging methods using radiations.
GARFIELD-AF risk score for mortality, stroke, and bleeding within 2 years in patients with atrial fibrillation
Authors: Fox Keith A A , Virdone Saverio , Pieper Karen S , Bassand Jean-Pierre , Camm A John , Fitzmaurice David A , Goldhaber Samuel Z , Goto Shinya , Haas Sylvia , Kayani Gloria , Oto Ali , Misselwitz Frank , Piccini Jonathan P , Dalgaard Frederik , Turpie Alexander G G , Verheugt Freek W A , Kakkar Ajay K ,   for the GARFIELD-AF Investigators
Published: April 2021

Aims

To determine whether the Global Anticoagulant Registry in the FIELD–Atrial Fibrillation (GARFIELD-AF) integrated risk tool predicts mortality, non-haemorrhagic stroke/systemic embolism, and major bleeding for up to 2 years after new-onset AF and to assess how this risk tool performs compared with CHA2DS2-VASc and HAS-BLED.

Methods and results

Potential predictors of events included demographic and clinical characteristics, choice of treatment, and lifestyle factors. A Cox proportional hazards model was identified for each outcome by least absolute shrinkage and selection operator methods. Indices were evaluated in comparison with CHA2DS2-VASc and HAS-BLED risk predictors. Models were validated internally and externally in ORBIT-AF and Danish nationwide registries. Among the 52 080 patients enrolled in GARFIELD-AF, 52 032 had follow-up data. The GARFIELD-AF risk tool outperformed CHA2DS2-VASc for all-cause mortality in all cohorts. The GARFIELD-AF risk score was superior to CHA2DS2-VASc for non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in internal validation and in the Danish AF cohort. In very low- to low-risk patients [CHA2DS2-VASc 0 or 1 (men) and 1 or 2 (women)], the GARFIELD-AF risk score offered strong discriminatory value for all the endpoints when compared to CHA2DS2-VASc and HAS-BLED. The GARFIELD-AF tool also included the effect of oral anticoagulation (OAC) therapy, thus allowing clinicians to compare the expected outcome of different anticoagulant treatment decisions [i.e. no OAC, non-vitamin K antagonist (VKA) oral anticoagulants, or VKAs].

Conclusions

The GARFIELD-AF risk tool outperformed CHA2DS2-VASc at predicting death and non-haemorrhagic stroke, and it outperformed HAS-BLED for major bleeding in overall as well as in very low- to low-risk group patients with AF.

Clinical trial registration

URL: http://www.clinicaltrials.gov. Unique identifier for GARFIELD-AF: NCT01090362, ORBIT-AF I: NCT01165710; ORBIT-AF II: NCT01701817.
Health impact of tafamidis in transthyretin amyloid cardiomyopathy patients: an analysis from the Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) and the open-label long-term extension studies
Authors: Rozenbaum Mark H , Garcia Andrea , Grima Daniel , Tran Diana , Bhambri Rahul , Stewart Michelle , Li Benjamin , Heeg Bart , Postma Maarten , Masri Ahmad
Published: April 2021

Aim

The Tafamidis in Transthyretin Cardiomyopathy Clinical Trial (ATTR-ACT) showed that tafamidis reduced all-cause mortality and cardiovascular-related hospitalizations in patients with transthyretin amyloid cardiomyopathy (ATTR-CM). This study aimed to estimate the impact of tafamidis on survival and quality-adjusted life-years (QALYs).

Methods and results

A multi-state, cohort, Markov model was developed to simulate the disease course of ATTR-CM throughout a lifetime. For survival extrapolation, survival curves were fitted by treatment arm and New York Heart Association (NYHA) Class I/II (68% of patients) and NYHA Class III (32% of patients) cohorts using the individual patient-level data from both the ATTR-ACT and the corresponding long-term extension study. Univariate and multivariate sensitivity analyses were conducted. The predicted mean survival for the total population (NYHA Class I/II + III) was 6.73 years for tafamidis and 2.85 years for the standard of care (SoC), resulting in an incremental mean survival of 3.88 years [95% confidence interval (CI) 1.32–5.66]. Of the 6.73 life-years, patients on tafamidis spend, on average, 4.82 years in NYHA Class I/II, while patients on SoC spend an average of 1.60 life-years in these classes. The combination of longer survival in lower NYHA classes produced a QALY gain of 5.39 for tafamidis and 2.11 for SoC, resulting in 3.29 incremental QALYs (95% CI 1.21–4.74) in favour of tafamidis.

Conclusion

Based on the disease simulation model results, tafamidis is expected to more than double the life expectancy and QALYs of ATTR-CM patients compared to SoC. Longer-term follow-up data from the ATTR-ACT extension study will further inform these findings.

Clinical trials.gov identifier

NCT01994889 (date of registration: 26 November 2013).
Epidemiological and clinical boundaries of heart failure with preserved ejection fraction
Authors: Gentile Francesco , Ghionzoli Nicolò , Borrelli Chiara , Vergaro Giuseppe , Pastore Maria Concetta , Cameli Matteo , Emdin Michele , Passino Claudio , Giannoni Alberto
Published: April 2021

Heart failure with preserved ejection fraction (HFpEF) is highly prevalent and is associated with relevant morbidity and mortality. However, an evidence-based treatment is still absent. The heterogeneous definitions, differences in aetiology/pathophysiology, and diagnostic challenges of HFpEF made it difficult to define its epidemiological landmarks so far. Several large registries and observational studies have recently disclosed an increasing incidence/prevalence, as well as its prognostic significance. An accurate definition of HFpEF epidemiological boundaries and phenotypes is mandatory to develop novel effective and rational therapeutic approaches.
Post-implementation perspectives on smokefree prison policy: a qualitative study with staff and people in custody
Authors: Brown Ashley , Mitchell Danielle , Hunt Kate
Published: April 2021

Background

A comprehensive smokefree prison policy (SFPP) was introduced in Scottish prisons from November 2018, reflecting concern about inequalities in occupational exposures to second-hand smoke (SHS) and tobacco-related harms among people in custody (PiC). We aimed to address a gap, whereby few studies have sought to understand SFPP from the perspectives of people living and working in prisons.

Methods

As part of a comprehensive evaluation, focus groups and interviews with staff (n = 99) and interviews with PiC (n = 23) were conducted 6–9 months post-implementation of SFPP in Scotland. Data were analysed using the framework approach.

Results

Our study found that new restrictions on smoking had been widely accepted by PiC, after a period of adjustment which was less troublesome than participants had anticipated. Benefits of the SFPP for the safety and comfort of staff and PiC who were no longer exposed to SHS, and additionally for the health of PiC who were now smoking-abstinent, were widely acknowledged. Drawbacks of the SFPP, such as difficulties managing without tobacco and use of alternatives (e.g. e-cigarettes and changes in use of illegal drugs), were also reported. Contraband tobacco was not reported to be a major problem following prisons becoming smokefree.

Conclusions

The findings strengthen evidence that SFPPs can be implemented without causing major disruption and highlight the need for removal of tobacco to be underpinned by careful planning, partnership working and ensuring the availability of support for smokers. Experiences from Scotland may be of interest and some comfort, internationally for jurisdictions considering smoke-free rules in prisons.
Diversity of cyanobacteria from thermal muds (Balaruc-Les-Bains, France) with the description of Pseudochroococcus coutei gen. nov., sp. nov.
Authors: Duval C , Hamlaoui S , Piquet B , Toutirais G , Yéprémian C , Reinhardt A , Duperron S , Marie B , Demay J , Bernard C
Published: April 2021

Cyanobacteria are able to synthesize a high diversity of natural compounds that account for their success in the colonization of a variety of ecological niches. Many of them have beneficial properties. The mud from the thermal baths of Balaruc-Les-Bains, one of the oldest thermal baths in France, has long been recognized as a healing treatment for arthro-rheumatic diseases. To characterize the cyanobacteria living in these muds, several strains were isolated from the water column and biofilms of the retention basin and analyzed using a polyphasic approach. Morphological, ultrastructural and molecular (16S rRNA gene and 16S-23S ITS region sequencing) methods were employed to identify nine cyanobacterial strains belonging to the orders Chroococcales, Synechococcales, Oscillatoriales and Nostocales. The combination of morphological and genetic characteristics supported the description of a new genus and species with the type species as Pseudochroococcus coutei. The taxonomic diversity in the muds from Thermes de Balaruc-Les-Bains appears higher than previously documented, providing new candidate taxa for their observed therapeutic properties.
Phylogenetic and Selection Analysis of an Expanded Family of Putatively Pore-Forming Jellyfish Toxins (Cnidaria: Medusozoa)
Authors: Klompen Anna M L , Kayal Ehsan , Collins Allen G , Cartwright Paulyn
Published: April 2021

Many jellyfish species are known to cause a painful sting, but box jellyfish (class Cubozoa) are a well-known danger to humans due to exceptionally potent venoms. Cubozoan toxicity has been attributed to the presence and abundance of cnidarian-specific pore-forming toxins called jellyfish toxins (JFTs), which are highly hemolytic and cardiotoxic. However, JFTs have also been found in other cnidarians outside of Cubozoa, and no comprehensive analysis of their phylogenetic distribution has been conducted to date. Here, we present a thorough annotation of JFTs from 147 cnidarian transcriptomes and document 111 novel putative JFTs from over 20 species within Medusozoa. Phylogenetic analyses show that JFTs form two distinct clades, which we call JFT-1 and JFT-2. JFT-1 includes all known potent cubozoan toxins, as well as hydrozoan and scyphozoan representatives, some of which were derived from medically relevant species. JFT-2 contains primarily uncharacterized JFTs. Although our analyses detected broad purifying selection across JFTs, we found that a subset of cubozoan JFT-1 sequences are influenced by gene-wide episodic positive selection compared with homologous toxins from other taxonomic groups. This suggests that duplication followed by neofunctionalization or subfunctionalization as a potential mechanism for the highly potent venom in cubozoans. Additionally, published RNA-seq data from several medusozoan species indicate that JFTs are differentially expressed, spatially and temporally, between functionally distinct tissues. Overall, our findings suggest a complex evolutionary history of JFTs involving duplication and selection that may have led to functional diversification, including variability in toxin potency and specificity.
Genetic Context Significantly Influences the Maintenance and Evolution of Degenerate Pathways
Authors: Bruger Eric L , Chubiz Lon M , Rojas Echenique José I , Renshaw Caleb J , Espericueta Nora Victoria , Draghi Jeremy A , Marx Christopher J
Published: April 2021

Understanding the evolution of novel physiological traits is highly relevant for expanding the characterization and manipulation of biological systems. Acquisition of new traits can be achieved through horizontal gene transfer (HGT). Here, we investigate drivers that promote or deter the maintenance of HGT-driven degeneracy, occurring when processes accomplish identical functions through nonidentical components. Subsequent evolution can optimize newly acquired functions; for example, beneficial alleles identified in an engineered Methylorubrum extorquens strain allowed it to utilize a “Foreign” formaldehyde oxidation pathway substituted for its Native pathway for methylotrophic growth. We examined the fitness consequences of interactions between these alleles when they were combined with the Native pathway or both (Dual) pathways. Unlike the Foreign pathway context where they evolved, these alleles were often neutral or deleterious when moved into these alternative genetic backgrounds. However, there were instances where combinations of multiple alleles resulted in higher fitness outcomes than individual allelic substitutions could provide. Importantly, the genetic context accompanying these allelic substitutions significantly altered the fitness landscape, shifting local fitness peaks and restricting the set of accessible evolutionary trajectories. These findings highlight how genetic context can negatively impact the probability of maintaining native and HGT-introduced functions together, making it difficult for degeneracy to evolve. However, in cases where the cost of maintaining degeneracy was mitigated by adding evolved alleles impacting the function of these pathways, we observed rare opportunities for pathway coevolution to occur. Together, our results highlight the importance of genetic context and resulting epistasis in retaining or losing HGT-acquired degenerate functions.
Mitochondrial Short-Term Plastic Responses and Long-Term Evolutionary Dynamics in Animal Species
Authors: Breton Sophie , Ghiselli Fabrizio , Milani Liliana
Published: April 2021

How do species respond or adapt to environmental changes? The answer to this depends partly on mitochondrial epigenetics and genetics, new players in promoting adaptation to both short- and long-term environmental changes. In this review, we explore how mitochondrial epigenetics and genetics mechanisms, such as mtDNA methylation, mtDNA-derived noncoding RNAs, micropeptides, mtDNA mutations, and adaptations, can contribute to animal plasticity and adaptation. We also briefly discuss the challenges in assessing mtDNA adaptive evolution. In sum, this review covers new advances in the field of mitochondrial genomics, many of which are still controversial, and discusses processes still somewhat obscure, and some of which are still quite speculative and require further robust experimentation.
The Asgard Archaeal-Unique Contribution to Protein Families of the Eukaryotic Common Ancestor Was 0.3%
Authors: Knopp Michael , Stockhorst Simon , van der Giezen Mark , Garg Sriram G , Gould Sven B
Published: April 2021

The identification of the asgard archaea has fueled speculations regarding the nature of the archaeal host in eukaryogenesis and its level of complexity prior to endosymbiosis. Here, we analyzed the coding capacity of 150 eukaryotes, 1,000 bacteria, and 226 archaea, including the only cultured member of the asgard archaea. Clustering methods that consistently recover endosymbiotic contributions to eukaryotic genomes recover an asgard archaeal-unique contribution of a mere 0.3% to protein families present in the last eukaryotic common ancestor, while simultaneously suggesting that this group’s diversity rivals that of all other archaea combined. The number of homologs shared exclusively between asgard archaea and eukaryotes is only 27 on average. This tiny asgard archaeal-unique contribution to the root of eukaryotic protein families questions claims that archaea evolved complexity prior to eukaryogenesis. Genomic and cellular complexity remains a eukaryote-specific feature and is best understood as the archaeal host’s solution to housing an endosymbiont.
Genomic Signature of Shifts in Selection and Alkaline Adaptation in Highland Fish
Authors: Tong Chao , Li Miao , Tang Yongtao , Zhao Kai
Published: April 2021

Understanding how organisms adapt to aquatic life at high altitude is fundamental in evolutionary biology. This objective has been addressed primarily related to hypoxia adaptation by recent comparative studies, whereas highland fish has also long suffered extreme alkaline environment, insight into the genomic basis of alkaline adaptation has rarely been provided. Here, we compared the genomes or transcriptomes of 15 fish species, including two alkaline tolerant highland fish species and their six alkaline intolerant relatives, three alkaline tolerant lowland fish species, and four alkaline intolerant species. We found putatively consistent patterns of molecular evolution in alkaline tolerant species in a large number of shared orthologs within highland and lowland fish taxa. Remarkably, we identified consistent signatures of accelerated evolution and positive selection in a set of shared genes associated with ion transport, apoptosis, immune response, and energy metabolisms in alkaline tolerant species within both highland and lowland fish taxa. This is one of the first comparative studies that began to elucidate the consistent genomic signature of alkaline adaptation shared by highland and lowland fish. This finding also highlights the adaptive molecular evolution changes that support fish adapting to extreme environments at high altitude.
GENETICALLY CONTROLLED VARIATION OF "ACID" β-GALACTOSIDASE DETECTED IN Rattus norvegicus BY ISOELECTRIC FOCUSING
Authors: Douglas Tommy C , Kimmel Kathryn A , Dawson Patti E
Published: April 2021

Two genetically variant forms of rat "acid" β-galactosidase were found to differ in isoelectric point and pH dependence, but not in thermostability or sensitivity to inhibition by p-mercuribenzoate (PMB). The results of two backcrosses and an intercross indicated that the isoelectric focusing phenotypes are controlled by two codominant alleles at a single autosomal locus, for which we propose the name Glb-1. No significant linkage between Glb-1 and albino (LG I), brown (LG II), or hooded (LG VI) was observed. Strain-specific differences in total levels of kidney β-galactosidase were detected, but it is not yet known whether the variation is controlled by genes linked to Glb-1. Experiments in which organ homogenates were incubated with neuraminidase indicated that the genetically variant forms do not result from differences in sialylation, though sialylation does appear to be largely responsible for the presence of multiple bands within each phenotype and for differences in the banding patterns of β-galactosidases derived from different organs. The β-galactosidase present in the bands used for Glb-1 typing resembles human GM1 gangliosidase (GLB1) with respect to pH optimum, substrate specificity, and susceptibility to inhibition by PMB. It also appears that Glb-1 is homologous with the Bgl-e locus of the mouse. In rats as in mice the genetically variant bands of β-galactosidase are active at acid pH and have relatively high isoelectric points. In both species these bands are readily detectable in kidney homogenates, and can be revealed in homogenates of liver or spleen following treatment with neuraminidase. The presence of the same β-galactosidase bands in homogenates of rat kidney and small intestine as well as in neuraminidase-treated homogenates of liver and spleen suggests that the Glb-1 variants differ by one or more point mutations in the structural gene for "acid" β-galactosidase.
GENIC INTERACTION CAUSING EMBRYONIC MORTALITY IN THE RAT: EPISTASIS BETWEEN THE Tal AND grc GENES
Authors: Schaid Daniel J , Kunz Heinz W , Gill Thomas J
Published: April 2021

The autosomal dominant mutant gene, tail anomaly lethal (Tal), of the rat is lethal when homozygous but affects tail morphology (kinks and reduced length) and body weight when heterozygous. There is no apparent sex effect on the expression of Tal. It is incompletely penetrant; has variable expressivity, which is influenced partly by its genetic background; and is not linked to the major histocompatibility complex (MHC). The heterozygous Tal gene and the homozygous grc genes, which are linked to the MHC and affect body size and fertility, interact to cause intrauterine death at a time between implantation (five to seven days post-fertilization) and 15 days of gestation. This interaction shifts the time of death from the immediate postnatal period when the homozygous grc genes act to the time during gestation when the homozygous Tal gene would cause death. This description of lethal epistatic interaction in the rat appears to be the first report of this phenomenon in mammals.
RECOMBINATION BETWEEN GENES LOCATED ON NONHOMOLOGOUS CHROMOSOMES IN SACCHAROMYCES CEREVISIAE
Authors: Mikus Margaret Dubay , Petes Thomas D
Published: April 2021

We constructed strains of Saccharomyces cerevisiae that contained two different mutant alleles of either the leu2 gene or the ura3 gene. These repeated genes were located on nonhomologous chromosomes; the two ura3- alleles were located on chromosomes V and XII and the two leu2- alleles were located on chromosomes III and XII. Genetic interactions between the two mutant copies of a gene were detected by the generation of either Leu+ or Ura+ revertants. Both spontaneous and ultraviolet irradiation-induced revertants were examined. By genetic and physical analysis, we have shown that Leu+ or Ura+ revertants can arise by a variety of different genetic interactions. The most common type of genetic interaction is the nonreciprocal transfer of information from one repeat to the other. We also detected reciprocal recombination between repeated genes, resulting in reciprocally translocated chromosomes.
GENETIC VARIATION IN THE EXPRESSION OF ADH IN DROSOPHILA MELANOGASTER
Authors: Maroni G , Laurie-Ahlberg C C , Adams D A , Wilton A N
Published: April 2021

Several chromosomes derived from natural populations have been identified that affect the expression of alcohol dehydrogenase (ADH) . Second chromosomes, which also carry the structural gene Adh, show a great deal of polymorphism of genetic elements that determine how much enzyme protein accumulates. The level of enzyme was measured in third instar larvae, 6-to-8-day-old males and in larval fat bodies and alimentary canals. In general, activities in the different organs and stages are highly correlated with one another. One line was found, however, in which the ADH level in the fat body is more than twice the level one would expect on the basis of the activity in alimentary canal. We have also found evidence of third-chromosome elements that affect the level of ADH.
Caenorhabditis elegans mutants defective in the functioning of the motor neurons responsible for egg laying.
Authors: Desai C , Horvitz H R
Published: April 2021

We have isolated and characterized 45 Caenorhabditis elegans mutants presumed to be defective in the functioning of the hermaphrodite-specific neurons (HSNs). Like hermaphrodites that lack the HSN motor neurons, these mutants are egg-laying defective and do not lay eggs in response to exogenous imipramine but do lay eggs in response to exogenous serotonin. Twenty of the 45 mutations define 10 new egl genes; the other 25 mutations are alleles of five previously defined genes, four of which are known to affect the HSNs. Seven mutations in three genes cause the HSNs to die in hermaphrodites, as they normally do in males. These genes appear to be involved in the determination of the sexual phenotype of the HSNs, and one of them (egl-41) is a newly identified gene that may function generally in sex determination. Five of the 15 genes are defined only by mutations that have dominant effects on egg laying. One gene egl(n1108), is defined by a temperature-sensitive allele that has a temperature-sensitive period after HSN development is complete, suggesting that egl(n1108) may be involved in HSN synaptic transmission. Four of the genes are defined by single alleles, which suggests that other such genes remain to be discovered. Mutations in no more than 4 of the 15 genes specifically affect the HSNs, indicating that there are few genes with functions needed only in this single type of nerve cell.
Chloroplast DNA variation in a wild plant, tolmiea menziesii.
Authors: Soltis D E , Soltis P S , Ranker T A , Ness B D
Published: April 2021

Few studies of cpDNA have provided evolutionary and/or phylogenetic information at the intraspecific level. We analyzed restriction site variation using 19 endonucleases in 37 populations representing both diploid (2n = 14) and autotetraploid (2n = 28) Tolmiea menziesii. Seven restriction site mutations and five length mutations were observed. Although diploid and tetraploid Tolmiea have been intensively studied using nuclear markers, cpDNA variation provided additional evolutionary insights not revealed previously. The chloroplast genomes of diploid and tetraploid Tolmiea are as distinct as those of many pairs of congeneric species of angiosperms. Based on outgroup comparisons, the primitive chloroplast genome is present in tetraploid rather than diploid Tolmiea. These findings suggest that either: (1) diploid and tetraploid Tolmiea may have diverged since the origin of the autotetraploid, (2) the original diploid donor of the cytoplasm present in the tetraploid subsequently became extinct, or (3) the diploid was actually derived from the tetraploid via polyhaploidy. cpDNA variation also revealed that despite their close geographic proximity, diploid and tetraploid Tolmiea do not experience cytoplasmic gene flow. Last, three cytoplasmically distinct groups of diploid populations exist, two of which occupy distinct geographic areas. These findings demonstrate that, at least in some plant species, restriction fragment analysis of cpDNA can provide important evolutionary and phylogenetic information at low taxonomic levels.
Genetics of dominant gibberellin-insensitive dwarfism in maize.
Authors: Harberd N P , Freeling M
Published: April 2021

D8 and Mpl1 are two dominant dwarfing mutations of maize. Although they differ in severity of dwarfism, both D8 and Mpl1 mutants are unresponsive to gibberellin (GA). Because of their close phenotypic resemblance to the recessive GA-sensitive dwarf mutants these dominant mutations may identify a gene whose product is involved in the reception of GA. With this possibility in mind we have studied the genetic properties of D8 and Mpl1. Both mutations map close to Adh1 on chromosome 1L. By marking normal and translocated 1L arms with different Adh1 electrophoretic mobility alleles, we investigated the effect of gene dosage on dominant dwarf phenotype. The results suggest that D8 and Mpl1 encode novel product functions and that these functions are relatively insensitive to the presence of the (presumed) wild-type product. Using X-ray induced chromosome breakage we created sectors of wild-type cells within D8 or Mpl1 tissue; these sectors were marked by the linked recessive lw mutation. The phenotypes of these sectors demonstrated that, at least in certain plant organs and tissues, dominant dwarfism can be an autonomous phenotype. These results are consistent with the hypothesis that the wild-type gene product acts as a GA receptor. The potential utility of dominant dwarf phenotype in plant developmental analysis is discussed, and possible mechanisms for the action of the D8 and Mpl1 mutations are considered.
Cloning of the DNA repair gene, uvsF, by transformation of Aspergillus nidulans.
Authors: Oza K , Käfer E
Published: April 2021

As a first step in the cloning of the DNA repair gene uvsF of Aspergillus nidulans, uvsF pyrG double mutant strains were transformed with a genomic library which carried the complementing Neurospora pyr-4 gene in the vector. Rare pyr+ uvs+ cotransformants were obtained on media lacking pyrimidines, overlayed with MMS (methyl-methane sulfonate) to which uvsF is hypersensitive. Among MMS-resistant transformants, Southerns revealed two types which showed single bands of different sizes when BglII-digested genomic DNA was probed with the vector. Both types produced uvsF- recombinants without vector sequences in homozygous crosses, but only those with the larger band also produced haploid uvs+ progeny. Using BglII-digested genomic DNA to transform Escherichia coli, plasmids of the corresponding two sizes could be rescued. Their inserts had a short internal region in common, giving evidence of rearrangement(s). In secondary transformation of uvsF mutants, only the plasmids with the larger insert showed complementation and these were used to screen Aspergillus libraries. Three types of genomic and two overlapping cDNA clones were identified. The cDNAs hybridized not only to each other, but also to the common region of the rescued plasmids. Therefore, cDNA subclones were used to map the putative uvsF sequences to a short segment in one genomic clone. In Northerns, the complementing large plasmid hybridized to three mRNAs, while the cDNA subclone identified one of these as the probable uvsF message.
Action of a transposable element in coding sequence fusions.
Authors: Shapiro J A , Leach D
Published: April 2021

The original Casadaban technique for isolating fused cistrons encoding hybrid beta-galactosidase proteins used a Mucts62 prophage to align the upstream coding sequence and lacZ prior to selection. Kinetic analysis of araB-lacZ fusion colony emergence indicated that the required DNA rearrangements were regulated and responsive to conditions on selection plates. This has been cited as an example of "directed mutation." Here we show genetically that the MuA and integration host factor (IHF) transposition functions are involved in the formation of hybrid araB-lacZ cistrons and propose a molecular model for how fusions can form from the initial strand-transfer complex. These results confirm earlier indications of direct Mu involvement in the fusion process. The proposed model explains how rearranged Mu sequences come to be found as interdomain linkers in certain hybrid cistrons and indicates that the fusion process involves a spatially and temporally coordinated sequence of biochemical reactions.
The unc-45 gene of Caenorhabditis elegans is an essential muscle-affecting gene with maternal expression.
Authors: Venolia L , Waterston R H
Published: April 2021

We have isolated three novel alleles of the unc-45 locus in C. elegans, that are recessive lethals. Two of these alleles, when homozygous, result in a nearly total loss of muscle contraction with a concomitant arrest of development and a displacement of muscle cells. The third allele is similar, but showed maternal rescue by a wild-type allele. All previously identified unc-45 alleles were temperature sensitive and, although they produced paralysis of adult animals, all were homozygous viable. Prior genetic studies with these temperature sensitive alleles had suggested that at least one function of the unc-45 gene product was to interact with the major myosin heavy chain isoform, MHC B, of body wall muscles. Our observations of the lethal alleles suggest that the unc-45 product normally interacts with additional muscle components in both the body wall and pharyngeal muscles. In particular, we suggest that the unc-45 product might interact with all four myosin heavy chains: MHC B; MHC A; and the pharyngeal isoforms, MHC C and MHC D. Maternal rescue of the lethality of the third allele shows that the unc-45 gene product is present in the oocytes, although it may not be necessary until late in development when myofilaments begin to assemble.
The effect of adaptive mutagenesis on genetic variation at a linked, neutral locus.
Authors: Colby C , Williams S M
Published: April 2021

Based on recent studies in single-celled organisms, it has been argued that a fitness benefit associated with a mutation will increase the probability of that mutation occurring. This increase is independent of mutation rates at other loci and is called adaptive mutagenesis. We modeled the effect of adaptive mutagenesis on populations of haploid organisms with adaptive mutation rates ranging from 0 to 1 x 10(-5). Allele frequencies at the selected locus and a neutral linked locus were tracked. We also observed the amount of linkage disequilibrium during the selective sweep and the final heterozygosity after the sweep. The presence of adaptive mutagenesis increases the number of genetic backgrounds carrying the new fitter allele, making the outcomes more representative of the population before the selection. Therefore, more neutral genetic variation is preserved in simulations with adaptive mutagenesis than in those without it due to hitchhiking. Since adaptive mutagenesis is time-dependent, it can generate mutants when other mechanisms of mutation cannot. In addition, adaptive mutagenesis has the potential to confound both phylogeny construction and the detection of natural selection from patterns of nucleotide variation.
Specialization of B-type cyclins for mitosis or meiosis in S. cerevisiae.
Authors: Dahmann C , Futcher B
Published: April 2021

The CLB1, CLB2, and CLB3 genes encode B-type cyclins important for mitosis in Saccharomyces cerevisiae, while a fourth B-type cyclin gene, CLB4, has no clear role. The effects of homozygous clb mutations on meiosis were examined. Mutants homozygous for clb1 clb3, or for clb1 clb4, gave high levels of sporulation, but produced mainly two-spored asci instead of four-spored asci. The cells had completed meiosis I but not meiosis II, producing viable diploid ascospores. CLB1 and CLB4 seem to be much more important for meiosis than for mitosis and may play some special role in meiosis II. In contrast, CLB2 is important for mitosis but not meiosis. The level of Cdc28-Clb activity may be important in determining whether meiosis II will occur.
Sequences required for paramutation of the maize b gene map to a region containing the promoter and upstream sequences.
Authors: Patterson G I , Kubo K M , Shroyer T , Chandler V L
Published: April 2021

The b gene encodes a transcriptional regulator of the maize anthocyanin biosynthetic pathway. Certain b alleles participate in paramutation, an allele-specific interaction that heritably alters transcription. The moderately transcribed B' allele heritably reduces the transcription of the highly transcribed B-I allele in a B'/B-I heterozygote, such that the B-I allele becomes B'. To identify the cis-acting sequences required for paramutation, we used B' or B-I alleles to isolate intragenic recombinants with B-Peru, an allele that is insensitive to paramutation and has distinct tissue-specific regulation. Physical mapping of the recombinant alleles showed that most of the crossovers were in a small region near the 5' end of the b-transcribed region. Analysis of the recombinant alleles revealed that the ability to cause and respond to paramutation and the control of tissue-specific expression both localize to the 5' region of the gene. The 3' boundary of these functions lies just upstream of the translation initiation codon. The 5' boundary has been estimated to be no more than 0.1 cM further upstream (1-150 kb). Thus, sequences critical for paramutation lie upstream of the b coding sequences and may include transcriptional regulatory sequences.
Testing heterozygote excess and deficiency.
Authors: Rousset F , Raymond M
Published: April 2021

Currently used tests of Hardy-Weinberg proportions do not take into account the nature of the alternative hypothesis, which is generally a heterozygote deficiency. Different exact tests, appropriate for small sample size and large number of alleles, are proposed in this perspective, and their properties are evaluated by power comparisons. Some tests are found to be close to optimal for the detection of inbreeding or heterozygote excess, one of which is a score test closely related to Robertson and Hill's estimator of the inbreeding coefficient. This test is also easily applied to multiple samples. Such tests are not always the most appropriate if alternative hypotheses differ from those considered here.
SELECTION AT THE HAPLOID AND DIPLOID PHASES: CYCLICAL VARIATION
Authors: Ewing Evelyn P
Published: April 2021

This paper considers a deterministic model, where selection acts at both the diploid and haploid phases of development. The stability criteria for the maintenance of a protected polymorphism are derived. The implications of the model are examined through several examples, with emphasis on the comparison of these conditions to those of models that view selection as acting only at the diploid or haploid phases. It is found that the consideration of both phases broadens the conditions over such models.
INDUCED DOMINANT LETHAL MUTATIONS AND CYTOTOXIC EFFECTS IN GERM CELLS OF DROSOPHILA MELANOGASTER WITH TRENIMON, PDMT AND SODIUM MONOFLUOROPHOSPHATE
Authors: Büchi Rudolf
Published: April 2021

Male and female Drosophila melanogaster with special sex chromosome or special autosome constitutions were fed with the mutagenic chemicals Trenimon (2,3,5-trisethyleneimino-1,4-benzoquinone) and PDMT (1-phenyl-3, 3-dimethyltriazene) and with the toxic substance Na2PO3F (sodium monofluorophosphate). The frequency of dominant lethality was recorded among the progeny. The results clearly show that dominant lethality is dose dependent for Trenimon- or PDMT-treated chromosomes in mature sperm and mature oocytes, and an increased amount of chromosomal material per nucleus yields an enhanced lethality. In contrast, a pure toxic effect of Na2PO3F on mature oocytes was demonstrated with one type of female.—With the stocks of Drosophila used, it is possible to distinguish between mutagenic and toxic effects of chemicals on the germ cells. Therefore, dominant lethality can be used as a simple and quick screening test for chemical mutagens.
BEHAVIORAL MUTANTS OF DROSOPHILA MELANOGASTER. I. ISOLATION AND MAPPING OF MUTATIONS WHICH DECREASE FLIGHT ABILITY
Authors: Homyk Theodore , Sheppard David E
Published: April 2021

A flight test box was developed and used in the isolation and initial characterization of Drosophila melanogaster mutants defective in flight behavior. Forty-eight mutants were isolated from F1 progeny of ethyl methanesulfonate-treated males. Genetic mapping and complementation tests show that the mutations reside at thirty-four different sites on the X chromosome. Different mutants show different degrees of flight ability compared to controls. Forty-six mutations are recessive, while two appear to be semi-dominant with respect to flight behavior. In addition to flight defects, five mutants have visible defects, five behave as temperature-sensitive lethals and three exhibit abnormal electro-retinograms. Alleles of each of the previously known behavioral mutations, Hyperkinetic, ether à go-go and Shaker were found. Preliminary studies also suggest that the flight behavioral phenotype of mutations at seven sites is affected by the temperature at which the flies develop.
GENETICS OF CYCLOHEXIMIDE RESISTANCE IN TETRAHYMENA
Authors: Bleyman Lea K , Bruns Peter J
Published: April 2021

Cycloheximide resistance in Tetrahymena is inducible by mutagenesis. Two mutations, isolated independently from genetically different strains, were analyzed. The two mutations, Chx-1 and Chx-2, were found to be alleles at the same locus. A specific analysis is presented which may serve as a model for strategies employing an independent manipulation of the micro- and macro-nuclei of this organism for genetic studies.
LYSOSOMAL ACID PHOSPHATASE DEFICIENCY: LIVER SPECIFIC VARIANT IN THE MOUSE
Authors: Lalley Peter A , Shows Thomas B
Published: April 2021

The number and classes of genes responsible for the final expression of lysosomal acid phosphatase were investigated in the mouse (Mus musculus). In mouse tissues, lysosomal acid phosphatase activity was separated by gel electrophoresis into two major zones of activity. The cathodal zone of activity in liver of the SM/J inbred strain was almost completely absent, while the anodal zone was increased in activity. Other tissues from SM/J were not affected, nor were livers and other tissues in 27 inbred mouse strains. Genetic studies indicated that this deficiency variant segregated as an autosomal codominant gene which has been designated Apl to symbolize the acid phosphatase liver phenotype. The Apl gene was not linked to markers on chromosomes 1, 2, 4, 5, 7, 8, or X. Electrophoretic, heat denaturation, neuraminidase treatment, tartrate inhibition studies and tissue mixing experiments suggested that the Aplgene was not a structural gene for acid phosphatase, but a separate gene that functions in liver and is responsible for controlling or modifying an acid phosphatase structural gene product.
DRIFT OR SELECTION: A STATISTICAL TEST OF GENE FREQUENCY VARIATION OVER GENERATIONS
Authors: Schaffer Henry E , Yardley Darrell , Anderson Wyatt W
Published: April 2021

The method used by Fisher and Ford (1947) to study the spread of a gene in a natural population has been modified to analyze the variation in allele frequencies from generation to generation in a common experimental procedure. A further analysis has been developed that is more sensitive to directional trends in the allele frequency over generations, and its use in detecting the action of directional selection on gene frequency at a locus is discussed. The power of each of these statistical tests is calculated for a number of cases, and the tests are applied to sets of isozyme data from Drosophila pseudoobscura and Zea mays.
THE NUMBER OF CHROMOSOMES IN SCHIZOSACCHAROMYCES POMBE: LIGHT MICROSCOPY OF STAINED PREPARATIONS
Authors: Robinow C F
Published: April 2021

Chromosomes have been counted with the light microscope in fixed and stained preparations of Schizosaccharomyces pombe. The least ambiguous images were seen in zygotes fixed at meta-, ana- and telophase of meiosis II. They suggest that the haploid number of chromosomes in S. pombe is three.
SPONTANEOUS AND ETHYL METHANESULFONATE-INDUCED MUTATIONS CONTROLLING VIABILITY IN DROSOPHILA MELANOGASTER. III. HETEROZYGOUS EFFECT OF POLYGENIC MUTATIONS
Authors: Ohnishi Ohmi
Published: April 2021

Spontaneous and EMS-induced mutations were accumulated for several generations on the second chromosome of Drosophila melanogaster by keeping this chromosome heterozygous under conditions of minimal natural selection. This article reports studies of heterozygous effects of these mutants.—Both lethal and mildly deleterious mutants have a deleterious heterozygous effect. There was no discernible difference between heterozygotes in which all the mutants were on one chromosome and those where the mutants were distributed over both homologs; thus the coupling-repulsion effect of Mukai and Yamazaki (1964, 1968) is not confirmed. The spontaneous polygenic mutants have a dominance of 0.4 to 0.5, and the same value is found at very low EMS doses. However, the value at higher EMS doses is only about half as high. Since the low doses have a large fraction of spontaneous mutants, the dominance of EMS mutants is less, in the range 0.1 to 0.3, but still larger than for lethals.
MULTILOCUS BEHAVIOR IN RANDOM ENVIRONMENTS. II. LINKAGE DISEQUILIBRIUM IN AN ADDITIVE MODEL
Authors: Gillespie John H
Published: April 2021

The effect of a stochastic environment on an additive, two-locus model of a diploid population is examined. The appropriate diffusion equation is derived and its asymptotic properties are approximated by an Orstein-Uhlenbeck process. The first and second order moments of this approximating process are given. The mean linkage disequilibrium will be nonzero if the alleles at the different loci are correlated. The sign of the mean disequilibrium is determined by the sign of the correlation.
INFLUENCE OF THE mat1-M ALLELE ON MEIOTIC RECOMBINATION IN THE MATING-TYPE REGION OF SCHIZOSACCHAROMYCES POMBE
Authors: Meade James H , Gutz Herbert
Published: April 2021

Angehrn and Gutz (1968) have shown that homozygosity for the mat1-M allele in diploid strains of Schizosaccharomyces pombe increases mitotic recombination between his7 and mat2. In this paper, we report that meiotic recombination frequencies can vary from 3.4 to 16.1 percent between his7 and his2 and that this variation is due to the combination of alleles at the mat1 and mat2 loci.
STATISTICAL STUDIES ON PROTEIN POLYMORPHISM IN NATURAL POPULATIONS II. GENE DIFFERENTIATION BETWEEN POPULATIONS
Authors: Chakraborty Ranajit , Fuerst Paul A , Nei Masatoshi
Published: April 2021

With the aim of testing the validity of the mutation-drift hypothesis, we examined the pattern of genetic differentiation between populations by using data from Drosophila, fishes, reptiles, and mammals. The observed relationship between genetic identity and correlation of heterozygosities of different populations or species was generally in good agreement with the theoretical expectations from the mutation-drift theory, when the variation in mutation rate among loci was taken into account. In some species of Drosophila, however, the correlation was unduly high. The relationship between the mean and variance of genetic distance was also in good agreement with the theoretical prediction in almost all organisms. We noted that both the distribution of heterozygosity within species and the pattern of genetic differentiation between species can be explained by the same set of genetic parameters in each group of organisms. Alternative hypotheses for explaining these observations are discussed.
TWENTY-SIX CHROMOSOMAL GENES NEEDED TO MAINTAIN THE KILLER DOUBLE-STRANDED RNA PLASMID OF SACCHAROMYCES CEREVISIAE
Authors: Wickner Reed B
Published: April 2021

The double-stranded RNA killer plasmid gives yeast strains carrying it both the ability to secrete a protein toxin and immunity to that toxin. This report describes a new series of mutants in chromsomal genes needed for killer plasmid maintenance (mak genes). These mutants comprise 12 complementation groups. There are a total of at least 26 mak genes. Each mak gene product is needed for plasmid maintenance in diploids as well as in haploids. None of these mak mutations prevent the killer plasmid from entering the mak  - spores in the process of meiotic sporulation. Complementation between mak mutants can be performed by mating meiotic spores from a makx/α plasmid-carrying diploid with a maky haploid. If x = y, about half the diploid clones formed lose the killer plasmid. If x # y, complementation occurs, and all of the diploid clones are killers.