bluuebunny/crossref_metadata_2025 huggingface dataset:
Beyond the average patient: how neuroimaging models can address heterogeneity in dementia
Authors: Verdi Serena , Marquand Andre F , Schott Jonathan M , Cole James H
Published: April 2021

Dementia is a highly heterogeneous condition, with pronounced individual differences in age of onset, clinical presentation, progression rates and neuropathological hallmarks, even within a specific diagnostic group. However, the most common statistical designs used in dementia research studies and clinical trials overlook this heterogeneity, instead relying on comparisons of group average differences (e.g. patient versus control or treatment versus placebo), implicitly assuming within-group homogeneity. This one-size-fits-all approach potentially limits our understanding of dementia aetiology, hindering the identification of effective treatments. Neuroimaging has enabled the characterization of the average neuroanatomical substrates of dementias; however, the increasing availability of large open neuroimaging datasets provides the opportunity to examine patterns of neuroanatomical variability in individual patients. In this update, we outline the causes and consequences of heterogeneity in dementia and discuss recent research that aims to tackle heterogeneity directly, rather than assuming that dementia affects everyone in the same way. We introduce spatial normative modelling as an emerging data-driven technique, which can be applied to dementia data to model neuroanatomical variation, capturing individualized neurobiological ‘fingerprints’. Such methods have the potential to detect clinically relevant subtypes, track an individual’s disease progression or evaluate treatment responses, with the goal of moving towards precision medicine for dementia.
Dissociable contributions of frontal and temporal brain regions to basic semantic composition
Authors: Graessner Astrid , Zaccarella Emiliano , Friederici Angela D , Obrig Hellmuth , Hartwigsen Gesa
Published: April 2021

Semantic composition is the ability to combine single words to form complex meanings and is an essential component for successful communication. Evidence from neuroimaging studies suggests that semantic composition engages a widely distributed left-hemispheric network, including the anterior temporal lobe, the inferior frontal gyrus and the angular gyrus. To date, the functional relevance of these regions remains unclear. Here, we investigate the impact of lesions to key regions in the semantic network on basic semantic composition. We conducted a multivariate lesion-behaviour mapping study in 36 native German speaking participants with chronic lesions to the language network after left-hemispheric stroke. During the experiment, participants performed a plausibility judgement task on auditorily presented adjective-noun phrases that were either meaningful (‘anxious horse’), anomalous (‘anxious salad’) or had the noun replaced by a pseudoword (‘anxious gufel’), as well as a single-word control condition (‘horse’). We observed that reduced accuracy for anomalous phrases is associated with lesions in left anterior inferior frontal gyrus, whereas increased reaction times for anomalous phrases correlates with lesions in anterior-to-mid temporal lobe. These results indicate that anterior inferior frontal gyrus is relevant for accurate semantic decisions, while anterior-to-mid temporal lobe lesions lead to slowing of the decision for anomalous two-word phrases. These differential effects of lesion location support the notion that anterior inferior frontal gyrus affords executive control for decisions on semantic composition while anterior-to-mid temporal lobe lesions slow the semantic processing of the individual constituents of the phrase.
Chemical storage of hydrogen in synthetic liquid fuels: building block for CO2-neutral mobility
Authors: Lee R P , Seidl L G , Meyer B
Published: April 2021

Green hydrogen is anticipated to play a major role in the decarbonization of the mobility sector. Its chemical storage in CO2-neutral synthetic liquid fuels is advantageous in terms of safety and reliability compared to other hydrogen storage developments, and thus represents a complementary building block to developments in electric and hydrogen mobility for the low-carbon transition in the mobility sector. Its development is especially relevant for transport sectors which will have no alternatives to liquid fuels in the foreseeable future. In this paper, three alternative technological routes for the chemical storage of hydrogen in CO2-neutral synthetic liquid fuels are identified and comparatively evaluated in terms of feedstock potential, product potential, demand for renewable electricity and associated costs, efficiency as well as expected market relevance. While all three routes exhibited similar levels of overall efficiencies, electricity-based liquid fuels in Germany are currently limited by the high cost and limited supply of renewable electricity. In contrast, liquid fuels generated from biogenic waste have a constant supply of biogenic feedstock and are largely independent from the supply and cost of renewable electricity.
AUTS2 Regulates RNA Metabolism and Dentate Gyrus Development in Mice
Authors: Castanza Anthony S , Ramirez Sanja , Tripathi Prem P , Daza Ray A M , Kalume Franck K , Ramirez Jan-Marino , Hevner Robert F
Published: April 2021

Human AUTS2 mutations are linked to a syndrome of intellectual disability, autistic features, epilepsy, and other neurological and somatic disorders. Although it is known that this unique gene is highly expressed in developing cerebral cortex, the molecular and developmental functions of AUTS2 protein remain unclear. Using proteomics methods to identify AUTS2 binding partners in neonatal mouse cerebral cortex, we found that AUTS2 associates with multiple proteins that regulate RNA transcription, splicing, localization, and stability. Furthermore, AUTS2-containing protein complexes isolated from cortical tissue bound specific RNA transcripts in RNA immunoprecipitation and sequencing assays. Deletion of all major functional isoforms of AUTS2 (full-length and C-terminal) by conditional excision of exon 15 caused breathing abnormalities and neonatal lethality when Auts2 was inactivated throughout the developing brain. Mice with limited inactivation of Auts2 in cerebral cortex survived but displayed abnormalities of cerebral cortex structure and function, including dentate gyrus hypoplasia with agenesis of hilar mossy neurons, and abnormal spiking activity on EEG. Also, RNA transcripts that normally associate with AUTS2 were dysregulated in mutant mice. Together, these findings indicate that AUTS2 regulates RNA metabolism and is essential for development of cerebral cortex, as well as subcortical breathing centers.
The voltage-gated potassium channel KV1.3 regulates neutrophil recruitment during inflammation
Authors: Immler Roland , Nadolni Wiebke , Bertsch Annika , Morikis Vasilios , Rohwedder Ina , Masgrau-Alsina Sergi , Schroll Tobias , Yevtushenko Anna , Soehnlein Oliver , Moser Markus , Gudermann Thomas , Barnea Eytan R , Rehberg Markus , Simon Scott I , Zierler Susanna , Pruenster Monika , Sperandio Markus
Published: April 2021

Aims

Neutrophil trafficking within the vasculature strongly relies on intracellular calcium signalling. Sustained Ca2+ influx into the cell requires a compensatory efflux of potassium to maintain membrane potential. Here, we aimed to investigate whether the voltage-gated potassium channel KV1.3 regulates neutrophil function during the acute inflammatory process by affecting sustained Ca2+ signalling.

Methods and results

Using in vitro assays and electrophysiological techniques, we show that KV1.3 is functionally expressed in human neutrophils regulating sustained store-operated Ca2+ entry through membrane potential stabilizing K+ efflux. Inhibition of KV1.3 on neutrophils by the specific inhibitor 5-(4-Phenoxybutoxy)psoralen (PAP-1) impaired intracellular Ca2+ signalling, thereby preventing cellular spreading, adhesion strengthening, and appropriate crawling under flow conditions in vitro. Using intravital microscopy, we show that pharmacological blockade or genetic deletion of KV1.3 in mice decreased neutrophil adhesion in a blood flow dependent fashion in inflamed cremaster muscle venules. Furthermore, we identified KV1.3 as a critical component for neutrophil extravasation into the inflamed peritoneal cavity. Finally, we also revealed impaired phagocytosis of Escherichia coli particles by neutrophils in the absence of KV1.3.

Conclusion

We show that the voltage-gated potassium channel KV1.3 is critical for Ca2+ signalling and neutrophil trafficking during acute inflammatory processes. Our findings do not only provide evidence for a role of KV1.3 for sustained calcium signalling in neutrophils affecting key functions of these cells, they also open up new therapeutic approaches to treat inflammatory disorders characterized by overwhelming neutrophil infiltration.
Computational models of atrial fibrillation: achievements, challenges, and perspectives for improving clinical care
Authors: Heijman Jordi , Sutanto Henry , Crijns Harry J G M , Nattel Stanley , Trayanova Natalia A
Published: April 2021

Despite significant advances in its detection, understanding and management, atrial fibrillation (AF) remains a highly prevalent cardiac arrhythmia with a major impact on morbidity and mortality of millions of patients. AF results from complex, dynamic interactions between risk factors and comorbidities that induce diverse atrial remodelling processes. Atrial remodelling increases AF vulnerability and persistence, while promoting disease progression. The variability in presentation and wide range of mechanisms involved in initiation, maintenance and progression of AF, as well as its associated adverse outcomes, make the early identification of causal factors modifiable with therapeutic interventions challenging, likely contributing to suboptimal efficacy of current AF management. Computational modelling facilitates the multilevel integration of multiple datasets and offers new opportunities for mechanistic understanding, risk prediction and personalized therapy. Mathematical simulations of cardiac electrophysiology have been around for 60 years and are being increasingly used to improve our understanding of AF mechanisms and guide AF therapy. This narrative review focuses on the emerging and future applications of computational modelling in AF management. We summarize clinical challenges that may benefit from computational modelling, provide an overview of the different in silico approaches that are available together with their notable achievements, and discuss the major limitations that hinder the routine clinical application of these approaches. Finally, future perspectives are addressed. With the rapid progress in electronic technologies including computing, clinical applications of computational modelling are advancing rapidly. We expect that their application will progressively increase in prominence, especially if their added value can be demonstrated in clinical trials.
Systematic Review: Sweet Syndrome Associated with Inflammatory Bowel Disease
Authors: Sleiman Joseph , Hitawala Asif A , Cohen Benjamin , Falloon Katie , Simonson Marian , Click Benjamin , Khanna Urmi , Fernandez Anthony P , Rieder Florian
Published: April 2021

Background and Aims

Sweet syndrome [SS] is a dermatological condition associated with both inflammatory bowel disease [IBD] and azathioprine use. We performed a systematic review to better delineate clinical characteristics and outcomes of SS in IBD patients.

Methods

Peer-reviewed, full-text journal publications from inception to April 2020 in English language and adult subjects with IBD were included. Skin biopsy was required as SS gold-standard diagnosis. Azathioprine-associated SS required recent azathioprine introduction or recurrence of SS after azathioprine re-challenge.

Results

We included 89 publications with 95 patients [mean age of SS diagnosis: 44 years; 59% female; 20 with azathioprine-associated SS and 75 without]. SS was diagnosed prior to IBD in 5.3%, at time of IBD diagnosis in 29.5% and after diagnosis in 64.2%. In total, 91% of patients with SS had known colonic involvement and the majority [76%] had active IBD at diagnosis; 22% had additional extra-intestinal manifestations. Successful therapies for SS included corticosteroids [90.5%], anti-tumour necrosis factor [TNF]-α inhibitor therapy [14.8%] and azathioprine [11.6%]. Azathioprine-associated SS was distinct, with 85% male patients, mean age of SS diagnosis of 50 years and a lower likelihood to be prescribed corticosteroids for treatment [75% vs 94.7% of non-azathioprine-associated SS, p = 0.008]. All patients with azathioprine-associated SS improved with medication cessation and developed recurrence after re-challenge.

Conclusions

SS may precede or occur with IBD diagnosis in almost one-third of cases. Azathioprine and IBD-associated SS present and behave distinctly, especially with regard to gender, age at diagnosis and recurrence risk. Corticosteroids and TNF-α inhibitors have demonstrated efficacy in treating SS in IBD.
Cluster analysis of emphysema for predicting pulmonary complications after thoracoscopic lobectomy
Authors: Tane Shinya , Nishikubo Megumi , Kitazume Mai , Fujibayashi Yusuke , Kimura Kenji , Kitamura Yoshitaka , Takenaka Daisuke , Nishio Wataru
Published: April 2021

OBJECTIVES

Despite significant advances in surgical techniques, including thoracoscopic approaches and perioperative care, the morbidity rate remains high after lung resection. This study focused on a low attenuation cluster analysis, which represented the size distribution of pulmonary emphysema and assessed its utility for predicting postoperative pulmonary complications after thoracoscopic lobectomy.

METHODS

From April 2013 to September 2018, lung cancer patients who received spirometry and computed tomography (CT) before surgery and underwent thoracoscopic lobectomy were included. The cumulative size distribution of the low attenuation area (LAA, defined as ≤−950 Hounsfield unit on CT) clusters followed a power-law characterized by an exponent D-value, a measure of the complexity of the alveolar structure. D-value and LAA% (LAA/total lung volume) were calculated using preoperative 3-dimensional CT software. The relationship between pulmonary complications and patient characteristics, including D-value and LAA%, was investigated.

RESULTS

Among 471 patients, there were 61 respiratory complication cases (12.9%). Receiver operation characteristic curve analysis revealed that the best predictive cut-off value of D-value and LAA% for pulmonary complications was 2.27 and 16.5, respectively, with an area under the curve of 0.72 and 0.58, respectively. D-value was significantly correlated with % forced expiratory volume in 1 s. Per univariate analysis, gender, smoking history, forced expiratory volume in 1 s/forced vital capacity, LAA% and D-value were risk factors for predicting postoperative pulmonary complications. In the multivariate analysis, D-value remained a significant predictive factor.

CONCLUSION

Preoperative assessment of emphysema cluster analysis may represent the vulnerability of the operated lung and could be the novel predictor for pulmonary complications after thoracoscopic lobectomy.
Alliance Embeddedness: Rodrigo Duterte and the Resilience of the US–Philippine Alliance
Authors: Winger Gregory
Published: April 2021

In 2016, Philippine President Rodrigo Duterte pledged to radically reorient Philippine foreign policy by separating from Manila's longtime ally the United States. Yet, this vaunted break with America has failed to manifest. Joint US–Philippine military activities have continued with President Duterte even singing the praises of his American partners. To understand how this about-face in Manila occurred, I conducted a detailed analysis of the first eighteen months of the Duterte administration. Drawing on primary sources and interviews with government officials from both countries, I argue that the continued vitality of the US–Philippine alliance stems not from disenchantment with China nor personal relationship between Duterte and Trump, but rather from an underlying institutional affinity engendered over decades of defense cooperation. Specifically, institutionalized cooperation within the alliance has cultivated a strong reservoir of support for the alliance within key institutions inside the Philippine government. This case not only highlights the development of the Duterte administration but also illustrates the wider ability of alliances to weather political discord by cultivating support within national bureaucracies.
PREFERENTIAL MATING IN SYMMETRIC MULTILOCUS SYSTEMS: STABILITY CONDITIONS OF THE CENTRAL EQUILIBRIUM
Authors: Karlin S , Raper J
Published: April 2021

Several multilocus models that incorporate both preferential mating and viability selection are studied. Specifically, a class of symmetric heterozygosity models are considered that assign individuals to phenotypic classes according to which loci are in heterozygous state regardless of the actual allelic content. Otherwise, an arbitrary number of loci, number of alleles per locus, and arbitrary recombination scheme, viability parameters and preferential mating pattern based on phenotypes are allowed. The conditions for the stability of a central polymorphism are indicated and interpreted. The effects of viability and preference selection may be summarized in a single quantity for each phenotypic class, a generalized fitness. Preferential assortative mating alone can produce stability for a central polymorphism as in the case of viability selection when sexual attractiveness or general fitness increases with higher levels of heterozygosity. The situation is more complex with sexual selection.
"ALTERNATE-2" DISJUNCTION DOES NOT EXIST
Authors: Boussy Ian A
Published: April 2021

John and Lewis (1965) proposed a model of disjunction of translocation heterozygotes that defined two types of alternate disjunction, alternate-1 and alternate-2, differing from the classic view of only one type. Endrizzi (1974), and subsequent workers citing him, claim to have observed two distinct alternate disjunction configurations, corresponding to John and Lewis's alternate—1 and alternate—2 types, in meiotic preparations of several species. These observations are based on a two-dimensional interpretation of the three-dimensional phenomenon of disjunction, and are erroneous. In each case the two supposed types are topologically identical. There is only one possible alternate disjunction configuration.
DETERMINATION OF THE ORDER OF GENE FUNCTION IN THE YEAST NUCLEAR DIVISION PATHWAY USING cs AND ts MUTANTS
Authors: Moir Don , Botstein David
Published: April 2021

Cold-sensitive (cs) and heat-sensitive (ts) conditional-lethal mutations that affect specifically the cell division cycle of budding yeast (Saccharomyces cerevisiae) were used to determine the order of gene function. Reciprocal temperature-shift experiments using cs-ts double mutants revealed a detailed order of function among genes whose execution points and mutant phenotypes are very similar. The data suggest that the nuclear branch of the overall cell-cycle pathway itself contains at least one branch.
FRAMESHIFT SUPPRESSION IN SACCHAROMYCES CEREVISIAE. IV. NEW SUPPRESSORS AMONG SPONTANEOUS CO-REVERTANTS OF THE GROUP II HIS4-206 AND LEU2-3 FRAMESHIFT MUTATIONS
Authors: Gaber Richard F , Culbertson Michael R
Published: April 2021

ICR-induced frameshift mutations at the his4 locus in Saccharomyces cerevisiae have been classified into several groups on the basis of their reversion and suppression properties. One group of externally suppressible his4 mutations, designated Group II, have been shown to contain +1 G:C insertions in glycine codons and are suppressed by any one of five suppressor mutations described previously (SUFI, SUF3, SUF4, SUF5, and SUP6). The suppressor genes are believed to encode glycine tRNAs containing four base anticodons. —-An analysis of spontaneous co-revertants of the Group II frameshift mutations his4-206 and leu2-3 has revealed the existence of eleven new Group II-specific suppressor genes (SUF15 through SlJF25). The locations of the new suppressor loci on the yeast genetic map have been determined. —-By comparing the ability or inability of Group II-specific suppressors mapping at 16 different loci to suppress different Group II his4 mutations, two subclasses of suppressors have been defined. One subclass suppresses his4-38 and his4-519, which contain the altered four base mRNA codons 5'-GGGU-3' and 5'-GGGG-3', respectively. The other subclass suppresses his4-38, but fails to suppress his4-519. The mechanism of tRNAmediated frameshift suppression and the molecular basis for this division of the suppressors into two subclasses is discussed.
Cytogenetic analysis of segregation distortion in Drosophila melanogaster: the cytological organization of the Responder (Rsp) locus.
Authors: Pimpinelli S , Dimitri P
Published: April 2021

The segregation distortion phenomenon occurs in Drosophila melanogaster males carrying an SD second chromosome and an SD+ homolog. In such males the SD chromosome is transmitted to the progeny more frequently than the expected 50% because of an abnormal differentiation of the SD+-bearing sperms. Three major loci are involved in this phenomenon: SD and Rsp, associated with the SD and SD+ chromosome, respectively, and E(SD). In the present work we performed a cytogenetic analysis of the Rsp locus which was known to map to the centromeric heterochromatin of the second chromosome. Hoechst- and N-banding techniques were used to characterize chromosomes carrying Responder insensitive (Rspi), Responder sensitive (Rsps) and Responder supersensitive (Rspss) alleles. Our results locate the Rsp locus to the h39 region of 2R heterochromatin. This region is a Hoechst-bright, N-banding negative heterochromatic block adjacent to the centromere. Quantitative variations of the h39 region were observed. The degree of sensitivity to Sd was found to be directly correlated with the physical size of that region, demonstrating that the Rsp locus is composed of repeated DNA.
Insertion of a copia element 5' to the Drosophila melanogaster alcohol dehydrogenase gene (adh) is associated with altered developmental and tissue-specific patterns of expression.
Authors: Strand D J , McDonald J F
Published: April 2021

The Drosophila melanogaster alcohol dehydrogenase gene (adh) is under the control of two separate promoters (proximal and distal) which are preferentially utilized at the larval and adult life stages, respectively. A variant alcohol dehydrogenase allele (RI-42) isolated from a natural population contains a copia retroviral-like transposable element inserted 240 bp upstream from the distal (adult) adh transcriptional start site. Levels of adh transcripts in the RI-42 variant are reduced in tissues and at life stages where copia is actively expressed and are affected in trans- by mutant alleles at the suppressor-of-white-apricot (su(wa] and suppressor-of-forked (su(f] loci. These suppressor genes have no effect on adh expression in wild-type Drosophila.
Linkage disequilibrium and genetic variances under mutation-selection balance.
Authors: Hastings A
Published: April 2021

I determine the contribution of linkage disequilibrium to genetic variances using results for two loci and for induced or marginal systems. The analysis allows epistasis and dominance, but assumes that mutation is weak relative to selection. The linkage disequilibrium component of genetic variance is shown to be unimportant for unlinked loci if the gametic mutation rate divided by the harmonic mean of the pairwise recombination rates is much less than one. For tightly linked loci, linkage disequilibrium is unimportant if the gametic mutation rate divided by the (induced) per locus selection is much less than one.
Models of quantitative variation of flux in metabolic pathways.
Authors: Keightley P D
Published: April 2021

As a model of variation in a quantitative character, enzyme activity variation segregating in a population is assumed to affect the flux in simple metabolic pathways. The genetic variation of flux is partitioned into additive and nonadditive components. An interaction component of flux variance is present because the effect of an allelic substitution is modified by other substitutions which change the concentrations of shared metabolites. In a haploid population, the the proportion of interaction variance is a function of the gene frequencies at the loci contributing to the flux variation, enzyme activities of mutant and wild type at variable loci and activities at nonvariable loci. The proportion of interaction variance is inversely related to the ratio of mutant to wild-type activities at the loci controlling the enzyme activities. The interaction component as a function of gene frequencies is at a maximum with high mutant allele frequencies. In contrast, the dominance component which would apply to a diploid population is maximal as a proportion of the total when mutant alleles are at low frequencies. Unless there are many loci with large differences in activity between the alleles, the interaction component is a small proportion of the total variance. Data on enzyme activity variation from natural and artificial populations suggest that such variation generates little nonadditive variance despite the highly interactive nature of the underlying biochemical system.
Physical analysis of spontaneous and mutagen-induced mutants of Escherichia coli K-12 expressing DNA exonuclease VIII activity.
Authors: Mahajan S K , Chu C C , Willis D K , Templin A , Clark A J
Published: April 2021

We have mapped the extents of two deletion sbcA mutations which result in production of DNA exonuclease VIII (ExoVIII). One mutation, sbcA8, deletes about 140 kb of DNA which includes most of the Rac prophage and the trg gene. Western blot analysis shows that the protein produced is larger than wild type ExoVIII. The nucleotide sequence shows that a translational gene fusion has occurred. The N-terminal 294 codons of recE have been deleted and the remaining C-terminal codons have been fused to the N-terminal portion of another reading frame we call sfcA. Analysis of the protein sequence encoded by sfcA shows an 83% similarity with rat and mouse NADP-linked malic enzyme. We discuss the possibility that sfcA is identical to maeA which encodes NAD-linked malic enzyme from Escherichia coli. Restriction nuclease analysis of a second deletion, sbcA81, by Southern blot technique indicates that about 105 kb of DNA have been deleted and a transcriptional gene fusion has occurred between recE and the regulatory region of an E. coli chromosomal gene. We also examined eight other sbc mutations that result in ExoVIII production. Five have no effect on restriction nucleotide fragment sizes detected by complementarity to lambda rev as probe. These are presumed point mutations. Three seem to produce additional restriction nucleotide fragments complementary to lambda rev. The possible nature of these sbc mutations is discussed.
Transvection in the Ultrabithorax domain of the bithorax complex of Drosophila melanogaster.
Authors: Mathog D
Published: April 2021

The phenotypes of several heterozygous combinations of mutations which map within the Ultrabithorax gene of Drosophila melanogaster are modulated by the extent of somatic homologous chromosome pairing, an effect known as transvection. One can discriminate between otherwise phenotypically similar mutations via their transvection behavior. This suggested the existence of previously undetected intragenic functional units. A collection of mutations has been classified into "transvection groups" (in analogy to complementation groups) on the basis of transvection tests with bithorax34e, postbithorax2, and Contrabithorax1 Ultrabithorax1. The conditions necessary for each transvection effect were determined from these transvection groups. The bithorax34e mutation only transvects with Ultrabithorax mutations with a contiguous Ultrabithorax transcriptional unit. In contrast, postbithorax2 transvection requires the distal part of the bithoraxoid region. As expected, Ultrabithorax mutations do not transvect with Contrabithorax1 Ultrabithorax1. However, it appears that this cross activation is not mediated solely through one of the known regulatory regions as mutations in these regions do not consistently block the response.
Molecular and phenotypic variation of the Zw locus region in Drosophila melanogaster.
Authors: Miyashita N T
Published: April 2021

Restriction map polymorphism in a 13-kb region of the Zw locus in Drosophila melanogaster was investigated for 64 X chromosome lines with seven 6-cutter and ten 4-cutter restriction enzymes. A total of 203 restriction sites were scored, of which 20 were found to be polymorphic. The estimated nucleotide variation for this region for overall data (pi = 0.003 and 0.001, and theta = 0.003 and 0.002, for 4-cutter and 6-cutter studies, respectively) was smaller than that reported for most regions studied in D. melanogaster. It was found that the Slow allozyme has a larger nucleotide variation and haplotype diversity than the Fast allozyme. Results suggest the relatively recent divergence of the Fast allozyme from the Slow allozyme. Glucose 6-phosphate dehydrogenase (G6PD) activity was measured as a phenotype of the Zw locus. A significant difference in G6PD activity between allozymes was detected. The between-line effect was highly significant within the Slow allozyme, but was not significant within the Fast allozyme. Although a direct causative link could not be established, these results suggest an association between the amounts of quantitative and molecular genetic variation at the Zw locus region.
Distance and pairing effects on the brownDominant heterochromatic element in Drosophila.
Authors: Henikoff S , Jackson J M , Talbert P B
Published: April 2021

We examined the behavior of the brownDominant (bwD) heterochromatic insertion moved to different locations relative to centric heterochromatin. Effects were measured as the degree of silencing of a wild-type brown eye pigment gene by bwD across a tandem duplication. A series of X-ray-induced effects were recovered at high frequency. Cis-acting enhancers were obtained by relocation of the duplication closer to autosomal heterochromatin. Enhancers were also recovered on the homologous chromosome when it was similarly rearranged, revealing a novel interhomologue effect whereby interactions occur between genetic elements near opposite ends of a chromosome arm rather than between paired alleles. Cis-acting suppressors were obtained as secondary rearrangements in which the duplication was moved farther away from heterochromatin. Suppression was correlated with loss of cytological association between bwD and the polytene chromocenter. Surprisingly, the distance from bwD to the chromocenter was not correlated with the strength of enhancement or suppression. We propose that bwD fails to coalesce with the chromocenter when its position along the chromosome places it beyond a threshold distance from heterochromatin, and this threshold depends upon the configuration of both the chromosome carrying bwD and its paired homologue.
Molecular and phenotypic characterization of a new mouse insertional mutation that causes a defect in the distal vertebrae of the spine.
Authors: Schrick J J , Dickinson M E , Hogan B L , Selby P B , Woychik R P
Published: April 2021

We have identified and characterized the phenotype of a new insertional mutation in one line of transgenic mice. Mice carrying this mutation, which we have designated TgN(Imusd)370Rpw, display undulations of the vertebrae giving rise to a novel kinky-tail phenotype. Molecular characterization of the insertion site indicates that the transgene integration has occurred without any substantial alterations in the structure of the host sequences. Using probes that flank the insertion site, we have mapped the mutation to chromosome 5 near the semidominant mutation, thick tail (Tht). Thick tail does not complement the TgN(Imusd)370Rpw mutation; compound mutants containing one copy of each mutation display a more severe phenotype than either mutation individually.
Genetic instability within monotonous runs of CpG sequences in Escherichia coli.
Authors: Bichara M , Schumacher S , Fuchs R P
Published: April 2021

Genetic information can be altered by base substitutions, frameshift mutations, and addition or deletion of nucleotides. Deletions represent an important class of genetic aberration occurring at DNA sequences where it is often possible to predict the existence of intermediates of mutation. Instability within tracts of repetitive sequence have recently been associated with several genetic disorders, including the so-called triplet repeat diseases and certain forms of colorectal cancers. In Escherichia coli, (GpC)n repetitive sequences have been shown to be deletion prone, but the precise mechanism of this mutagenic pathway is still unknown. We show here that interrupting the monotony of the (GpC)n run with an ApT or a GpT dinucleotide decreases the rate of deletions within these sequences. On the other hand, introducing purine-pyrimidine alternating sequences beside the GpC insert results in an increased rate of deletion. Two pathways can be envisioned: (1) (GpC)n tracts can be seen as potential Z-forming DNA sequences, and this unusual DNA structure can be processed by an unknown cellular mechanism to give rise to the observed deletions and (2) (GpC)n monotonous runs can be considered as a succession of direct or palindromic repeats, allowing formation of DNA structures that are known to participate to frameshift mutagenesis. The results presented in this article are discussed in the light of these two alternative pathways.
RTM1: a member of a new family of telomeric repeated genes in yeast.
Authors: Ness F , Aigle M
Published: April 2021

We have isolated a new yeast gene called RTM1 whose overexpression confers resistance to the toxicity of molasses. The RTM1 gene encodes a hydrophobic 34-kD protein that contains seven potential transmembrane-spanning segments. Analysis of a series of industrial strains shows that the sequence is present in multiple copies and in variable locations in the genome. RTM loci are always physically associated with SUC telomeric loci. The SUC-RTM sequences are located between X and Y' subtelomeric sequences at chromosome ends. Surprisingly RTM sequences are not detected in the laboratory strain X2180. The lack of this sequence is associated with the absence of any SUC telomeric gene previously described. This observation raises the question of the origin of this nonessential gene. The particular subtelomeric position might explain the SUC-RTM sequence amplification observed in the genome of yeasts used in industrial biomass or ethanol production with molasses as substrate. This SUC-RTM sequence dispersion seems to be a good example of genomic rearrangement playing a role in evolution and environmental adaptation in these industrial yeasts.
The diversity of alleles at the hsd locus in natural populations of Escherichia coli.
Authors: Barcus V A , Titheradge A J , Murray N E
Published: April 2021

In enteric bacteria three discrete families of type I restriction and modification systems (IA, IB and ID) are encoded by alleles of the serB-linked hsd locus. Probes specific for each of the three families were used to monitor the distribution of related systems in 37 of the 72 wild-type Escherichia coli strains comprising the ECOR collection. All 25 members of group A in this collection were screened; 12 were probe-positive, nine have hsd genes in the IA family, two in the IB and one in the ID. Twelve strains, representing all groups other than A, were screened; five were probe-positive, one has hsd genes in the IA family, one in the IB and three in the ID. The type ID genes are the first representatives of this family in E. coli, the probe-negative strains could have alternative families of hsd genes. The type IA and IB systems added at least five new specificities to the five already identified in natural isolates of E. coli. The distribution of alleles is inconsistent with the dendrogram of the bacterial strains derived from other criteria. This discrepancy and the dissimilar coding sequences of allelic hsd genes both imply lateral transfer of hsd genes.
Wolbachia infections and the expression of cytoplasmic incompatibility in Drosophila sechellia and D. mauritiana.
Authors: Giordano R , O'Neill S L , Robertson H M
Published: April 2021

Various stocks of Drosophila mauritiana and D. sechellia were found to be infected with Wolbachia, a Rickettsia-like bacterium that is known to cause cytoplasmic incompatibility and other reproductive abnormalities in arthropods. Testing for the expression of cytoplasmic incompatibility in these two species showed partial incompatibility in D. sechellia but no expression of incompatibility in D. mauritiana. To determine whether absence of cytoplasmic incompatibility in D. mauritiana was due to either the bacterial or host genome, we transferred bacteria from D. mauritiana into an uninfected strain of D. simulans, a host species known to express high levels of incompatibility with endogenous Wolbachia. We also performed the reciprocal transfer of the natural D. simulans Riverside infection into a tetracycline-treated stock of D. mauritiana. In each case, the ability to express incompatibility was unaltered by the different host genetic background. These experiments indicate that in D. simulans and D. mauritiana expression of the cytoplasmic incompatibility phenotype is determined by the bacterial strain and that D. mauritiana harbors a neutral strain of Wolbachia.
Spatial distributions of genotypes under isolation by distance.
Authors: Epperson B K
Published: April 2021

The spatial distributions of single-locus diploid genotypes, produced within populations of sexually reproducing individuals under isolation by distance, are measured and characterized in detail by quantifying the join-counts for simulated model populations. The models more realistically reflect spatially explicit distributions of genotypes in populations, because unlike the classical theory, they include the stochasticity inherent in the process of matings between genotypes. This stochasticity causes the formation of large areas or patches containing mostly one homozygous genotype, which is not predicted by the classical theory. A number of previously uncharacterized features of the spatial structures produced under isolation by distance are revealed. Spatial autocorrelation measures based on counts of pairs of homozygotes are highly consistent quantifications of the concentrations of homozygotes in patchy genotypic distributions for a given level of dispersal. Most strikingly, the degree of intermixing of homozygotes with heterozygotes over small spatial scales is much higher than previously thought, unless dispersal is extremely limited (e.g., Wright's neighborhood size less than approximately 5.0). Among implications for studies of spatial structure of real populations, one is that the results provide a basis for using join-counts as estimators of gene dispersal based solely on genetic data.
GENETIC LOAD AND VIABILITY DISTRIBUTION IN CENTRAL AND MARGINAL POPULATIONS OF DROSOPHILA SUBOBSCURA
Authors: Sperlich Diether , Feuerbach-Mravlag Heide , Lange Peter , Michaelidis Apostolos , Pentzos-Daponte Athena
Published: April 2021

Relative viabilities of individuals homozygous or randomly heterozygous for wild O chromosomes derived from a marginal (Norwegian) and a central (Greek) population of D. subobscura were obtained by means of a newly prepared marker strain. In the central and marginal populations 20.8 and 28.8 percent of all chromosomes proved lethal or semilethal in homozygous condition. Mean viability was higher for +/+ random heterozygotes than for +/+ homozygotes. This remained the case for the marginal, but not for the central populations, after exclusion of the detrimental chromosomes from the calculations. The variances of viabilities were higher for homozygotes than for heterozygotes, but the test crosses with chromosomes from the marginal population had generally higher variances than those with chromosomes from the central population. No correlation was found in either populations between the action of a chromosome in homozygous condition with its action in heterozygous condition. This is interpreted as complete recessiveness of genetic load. The results are discussed in terms of the observed reduction of the inversion polymorphism which is not paralleled by a reduction in enzyme and, as shown here, by reduction in viability variation. It is thought that the heterotic effect of inversions is due to their homeostatic action, which depends less on structural genes than on higher orders of organization due to gene interaction or regulation. Whatever the causes, it is very likely that marginal populations differ from central populations with respect to their genetic system.
ESTIMATES OF GENETIC PARAMETERS OF BODY WEIGHT IN DESCENDANTS OF X-IRRADIATED RAT SPERMATOGONIA
Authors: Gianola Daniel , Chapman A B , Rutledge J J
Published: April 2021

Effects of nine generations of 450r per generation of ancestral spermatogonial X irradiation of inbred rats on genetic parameters of body weight at 3, 6 and 10 weeks of age and of weight gains between these periods were studied. Covariances among relatives were estimated by mixed model and regression techniques in randomly selected lines with (R) and without (C) radiation history. Analyses of the data were based on five linear genetic models combining additive direct, additive indirect (maternal), dominance and environmental effects. Parameters in these models were estimated by generalized least-squares. A model including direct and indirect genetic effects fit more closely to the data in both R and C lines. Overdominance of induced mutations did not seem to be present. Ancestral irradiation increased maternal additive genetic variances of body weights and gains but not direct genetic variances. Theoretically, due to a negative direct-maternal genetic correlation, within full-sib family selection would be ineffective in increasing body weight at six weeks in both R and C lines. However, progress from mass selection would be expected to be faster in the R lines.
EVALUATION OF THE STEPWISE MUTATION MODEL OF ELECTROPHORETIC MOBILITY: COMPARISON OF THE GEL SIEVING BEHAVIOR OF ALLELES AT THE ESTERASE-5 LOCUS OF DROSOPHILA PSEUDOOBSCURA
Authors: Johnson George B
Published: April 2021

Seven alleles at the esterase-5 locus of Drosophila pseudoobscura appear approximately uniformly spaced on 5% acrylamide gels. Such stepwise "ladders" in mobility have been used to argue for the charge-state model of electrophoretic mobility. To evaluate this interpretation, flies of the seven strains were examined in replicate electrophoresis on polyacrylamide gels of differing pore size, permitting estimation of the relative contributions of charge and of size/conformation to electrophoretic mobility. Six of the seven strains examined proved to be heterogeneous, containing multiple variants that migrate to similar positions on 5% acrylamide gels. In the one strain genetically analyzed to date, the hidden variants segregate in crosses. A total of fourteen variants are detected by this gel sieving analysis, many of them involving apparent conformational differences. Thus, protein properties in addition to net charge appear to play an important role in determining the degree of mobility difference between alleles. Examining estimates of free mobility, uniform charge differences are the rule within conformational classes. However, the superposition of conformational heterogeneity renders interpretation of mobility spacing solely in terms of such charge differences inappropriate.
THE POPULATION BIOLOGY OF BACTERIAL PLASMIDS: A PRIORI CONDITIONS FOR THE EXISTENCE OF CONJUGATIONALLY TRANSMITTED FACTORS
Authors: Stewart Frank M , Levin Bruce R
Published: April 2021

A mathematical model for the population dynamics of conjugationally transmitted plasmids in bacterial populations is presented and its properties analyzed. Consideration is given to nonbacteriocinogenic factors that are incapable of incorporation into the chromosome of their host cells, and to bacterial populations maintained in either continuous (chemostat) or discrete (serial transfer) culture. The conditions for the establishment and maintenance of these infectious extrachromosomal elements and equilibrium frequencies of cells carrying them are presented for different values of the biological parameters: population growth functions, conjugational transfer and segregation rate constants. With these parameters in a biologically realistic range, the theory predicts a broad set of physical conditions, resource concentrations and dilution rates, where conjugationally transmitted plasmids can become established and where cells carrying them will maintain high frequencies in bacterial populations. This can occur even when plasmid-bearing cells are much less fit (i.e., have substantially lower growth rates) than cells free of these factors. The implications of these results and the reality and limitations of the model are discussed and the values of its parameters in natural populations speculated upon.
ELECTROPHORETIC VARIATION FOR X-CHROMOSOME-LINKED PHOSPHOGLYCERATE KINASE (PGK-1) IN THE MOUSE
Authors: Nielsen J T , Chapman V M
Published: April 2021

Electrophoretic variation for X-chromosome-linked phosphoglycerate kinase (PGK-1) has been found as a polymorphism in feral mice in Denmark. Males from feral sampling or from a variety of genetic crosses have only a single-banded phenotype of the variant PGK-1A type or of the PGK-1B type commonly found among inbred mice. By contrast, three phenotypes were observed among females; two homozygous single-banded types and a heterozygous double-banded type. The X-chromosome linkage of the Pgk-1 locus was determined from the mode of inheritance in F1 and backcross generations and confirmed by the linkage of Pgk-1 and the X-linked markers Hq, Ta and Mo. Pgk-1 showed 29/122 recombinations with Hq, 5/185 with Ta and 0/108 recombinants with Mo. Based on these recombination data, a gene order of Hq—Ta—Pgk-1—Mo is suggested.
GENETIC MAPPING IN SCHIZOSACCHAROMYCES POMBE BY MITOTIC AND MEIOTIC ANALYSIS AND INDUCED HAPLOIDIZATION
Authors: Kohli Jürg , Hottinger Herbert , Munz Peter , Strauss Andre , Thuriaux Pierre
Published: April 2021

The genetic maps of the fission yeast Schizosaccharomyces pombe were extended through the use of haploidization (spontaneous or induced by m-fluorophenylalanine), as well as by tetrad, random spore and mitotic analysis. A new diploidization method utilizing a meiosis-deficient mutant and improved haploidization techniques was employed. As a result of these and previous studies, 118 genetic markers have been assigned to 3 linkage groups. Centromere markers for all 3 chromosomes were identified and genetic maps containing a total of 71 genes were constructed. Our experiments indicate that 3 is very likely to be the haploid chromosome number of S. pombe.
AN EXPERIMENTAL INVESTIGATION OF THE UNIT CHARGE MODEL OF PROTEIN POLYMORPHISM AND ITS RELATION TO THE ESTERASE-5 LOCUS OF DROSOPHILA PSEUDOOBSCURA, DROSOPHILA PERSIMILIS, AND DROSOPHILA MIRANDA
Authors: Cobbs Gary , Prakash Satya
Published: April 2021

The relationship between charge changes and electrophoretic mobility changes is investigated experimentally. The charge of several proteins is altered by reaction with small molecules of known structure and the change in electrophoretic mobility is measured. The method of Ferguson plots is used to separate charge and shape components of mobility differences. The average effect of an amino acid charge change on the mobility of the esterase-51.00 allele of Drosophila pseudoobscura is estimated to be 0.046. This estimate is then used to apply the step model of Ohta and Kimura (1973) to electrophoretic mobility data for the esterase-5 locus of D. pseudoobscura and D. miranda. The variation in electrophoretic mobility at this locus was found to be in agreement with the predictions of the step model.