bluuebunny/crossref_metadata_2025 huggingface dataset:
Individual changes in anthropometric measures after age 60 years: a 15-year longitudinal population-based study
Authors: Guo Jie , Shang Ying , Fratiglioni Laura , Johnell Kristina , Welmer Anna-Karin , Marseglia Anna , Xu Weili
Published: February 2021

Background

weight loss is commonly observed with ageing. We explored the trajectory of body mass index (BMI) and two proxies of muscle mass—calf circumference (CC) and mid-arm circumference (MAC)—and identified their determinants.

Methods

within the SNAC-K cohort, 2,155 dementia-free participants aged ≥60 years were followed over 15 years. BMI, CC and MAC were measured at baseline and follow-ups. Baseline sociodemographic and lifestyle factors were collected through interviews. Diabetes and vascular disorders were diagnosed by physicians through clinical examination and medical records. Data were analysed using linear mixed-effect models stratified by age (younger-old [<78 years] vs. older-old [≥78 years]).

Results

over the 15-year follow-up, BMI remained stable among participants aged 60 years at baseline (βslope = 0.009 [95% confidence interval −0.006 to 0.024], P = 0.234) and declined significantly among those aged ≥66 years, while CC and MAC declined significantly across all age groups. The decline over 15 years in BMI, CC and MAC separately was 0.435 kg/m2, 1.110 cm and 1.455 cm in the younger-old and was 3.480 kg/m2, 3.405 cm and 3.390 cm in the older-old. In younger-old adults, higher education was associated with slower declines in all three measures, while vascular disorders and diabetes were associated with faster declines. In older-old adults, vigorous physical activity slowed declines in BMI and CC, while vascular disorders accelerated declines in BMI and MAC.

Conclusions

CC and MAC declined earlier and more steeply than BMI. Cardiometabolic disorders accelerated such declines, while higher education and physical activity could counteract those declines.
Patterns of multimorbidity and their association with hospitalisation: a population-based study of older adults in urban Tanzania
Authors: Tomita Andrew , Leyna Germana H , Kim Hae-Young , Moodley Yoshan , Mpolya Emmanuel , Mogeni Polycarp , Cuadros Diego F , Dzomba Armstrong , Vandormael Alain , Bärnighausen Till , Tanser Frank
Published: February 2021

Background

while the HIV epidemic remains a considerable challenge in sub-Saharan Africa, a dramatic reduction in the associated mortality has led to a fundamental shift in the public health priorities aimed at tackling multimorbidity. Against the unprecedented level of urbanisation taking place in Tanzania, the burden of multimorbidity and its consequences among ageing adults, in the form of costly inpatient hospitalisation, remain unquantified.

Methods

we used data from one of Africa’s largest urban population cohort, the Dar es Salaam Health and the Demographic Surveillance System, to quantity the extent of multimorbidity (occurrence of 2 ≥ health conditions) and discordant multimorbidity (occurrence of conditions in 2 ≥ domains in mental health, non-communicable and communicable health) among 2,299 adults aged ≥40 years in Dar es Salaam, Tanzania. We fitted logistic regression models to investigate the association between multimorbidity and inpatient hospitalisation.

Results

the prevalence of multimorbidity and discordant multimorbidity were 25.3 and 2.5%, respectively. Although the severe forms of multimorbidity (2.0% with ≥4 health conditions) and discordancy were low, hospitalisation was significantly higher based on the regression analyses. Household food insecurity was the only socio-economic variable that was significantly and consistently associated with a greater hospitalisation.

Conclusion

we found an alarmingly high degree of multimorbidity among this ageing urban population where hospitalisation was driven by multimorbidity. As public health resources remain scarce, reducing costly inpatient hospitalisation requires multilevel interventions that address clinical- and structural-level challenges (e.g. food insecurity) to mitigate multimorbidity and promote long-term healthy independent living among older adults in Tanzania.
Rabbis of the (Scientific) Revolution: Revealing the Hidden Corpus of Early Modern Translations Produced by Jewish Religious Thinkers
Authors: Idelson-Shein Iris
Published: February 2021

This essay discusses the corpus of translations of non-Jewish texts into Jewish languages, which emerged during the early modern period. Particular attention is given to Hebrew translations produced by members of the Jewish religious elite during the long eighteenth century, which have hitherto been viewed as original Jewish works. The article argues that translation was perfectly suited to the combination of attraction and anxiety with which many early modern Jews, particularly members of the Jewish religious elite, observed the cultural developments of their time. These authors acknowledged (what they viewed as) their own cultural inferiority, but feared the potential hazards of direct exposure to non-Jewish texts and ideas. Jewish translators thus became cultural gatekeepers rather than passive recipients of non-Jewish culture. They mistranslated both deliberately and accidentally, added and omitted, gave new meanings to texts and ideas, and harnessed their sources to meet their own agendas. The works of these translators reveal a form of cultural transfer that relied on the mindful adaptation and reformulation of new ideas by discreet, almost inadvertent innovators.
Individual Uniqueness in the Neonatal Functional Connectome
Authors: Wang Qiushi , Xu Yuehua , Zhao Tengda , Xu Zhilei , He Yong , Liao Xuhong
Published: February 2021

The functional connectome is highly distinctive in adults and adolescents, underlying individual differences in cognition and behavior. However, it remains unknown whether the individual uniqueness of the functional connectome is present in neonates, who are far from mature. Here, we utilized the multiband resting-state functional magnetic resonance imaging data of 40 healthy neonates from the Developing Human Connectome Project and a split-half analysis approach to characterize the uniqueness of the functional connectome in the neonatal brain. Through functional connectome-based individual identification analysis, we found that all the neonates were correctly identified, with the most discriminative regions predominantly confined to the higher-order cortices (e.g., prefrontal and parietal regions). The connectivities with the highest contributions to individual uniqueness were primarily located between different functional systems, and the short- (0–30 mm) and middle-range (30–60 mm) connectivities were more distinctive than the long-range (>60 mm) connectivities. Interestingly, we found that functional data with a scanning length longer than 3.5 min were able to capture the individual uniqueness in the functional connectome. Our results highlight that individual uniqueness is present in the functional connectome of neonates and provide insights into the brain mechanisms underlying individual differences in cognition and behavior later in life.
Viral Reservoir in Early-Treated Human Immunodeficiency Virus-Infected Children and Markers for Sustained Viral Suppression
Authors: Ajibola Gbolahan , Garcia-Broncano Pilar , Maswabi Kenneth , Bennett Kara , Hughes Michael D , Moyo Sikhulile , Mohammed Terrence , Jean-Philippe Patrick , Sakoi Maureen , Batlang Oganne , Lockman Shahin , Makhema Joseph , Kuritzkes Daniel R , Lichterfeld Mathias , Shapiro Roger L
Published: February 2021

Background

The impact of very early infant treatment on human immunodeficiency virus (HIV) reservoir, and markers for treatment success, require study.

Methods

The Early Infant Treatment Study (EIT) enrolled 40 children living with HIV started on antiretroviral treatment (ART) at <7 days of age, with 23 who had started treatment between 30–365 days to serve as controls. Quantitative HIV DNA was evaluated every 1–3 months in peripheral blood mononuclear cells. 84-week repeat qualitative whole blood DNA polymerase chain reaction and dual enzyme immunosorbent assay were performed.

Results

Median quantitative cell-associated DNA after at least 84 weeks was significantly lower among the first 27 EIT children tested than among 10 controls (40.8 vs 981.4 copies/million cells; P < .001) and correlated with pre-ART DNA. Median DNA after 84 weeks did not differ significantly by negative or positive serostatus at 84 weeks (P = .94), and appeared unaffected by periods of unsuppressed plasma RNA from 24–84 weeks (P = .70). However, negative 84-week serostatus was 67% predictive for sustained RNA suppression, and positive serostatus was 100% predictive for viremia. Loss of qualitative DNA positivity at 84 weeks was 73% predictive for sustained suppression, and persistent positivity was 77% predictive for viremia.

Conclusions

Lower viral reservoir was associated with starting ART at <1 week. Negative serostatus and qualitative DNA were useful markers of sustained viral suppression from 24–84 weeks.
Myeloid bodies caused by COQ2 mutation: a case of concurrent COQ2 nephropathy and IgA nephropathy
Authors: Ni Hai-Feng , Yang Yan , Li Chun-Qing , Zhou Tong-Zhou , Liu Bi-Cheng , Wang Bin
Published: February 2021

Immunoglobulin A (IgA) nephropathy, in the presence of myeloid bodies, has been reported in Fabry disease (FD). In this case, we excluded the diagnosis of FD by demonstrating the absence of mutation in the α-galactosidase A（GLA）gene. Our patient also denied any history of use of cationic amphiphilic drugs. Interestingly, we identified a novel missense mutation for Coenzyme Q2（COQ2） , which is known to cause COQ2 mutation-associated nephropathy. We also found heteromorphic mitochondria and good treatment response in our patient following coenzyme Q10 supplementation. In light of our findings, our patient was diagnosed with COQ2 nephropathy and IgA nephropathy. To our knowledge, this is the first case report of COQ2 nephropathy with pathologic manifestations of myeloid bodies in podocytes.
Cardiac troponin and infective endocarditis prognosis: a systematic review and meta-analysis
Authors: Postigo Andrea , Vernooij Robin W M , Fernández-Avilés Francisco , Martínez- Sellés Manuel
Published: February 2021

Aims

Infective endocarditis (IE) is associated with high mortality and morbidity. Cardiac troponin (Tn) elevation seems to be common in patients with IE and could be associated with a poor prognosis. The aim of this study was to synthesize the prognostic value of Tn in patients with IE.

Methods and results

We searched in MEDLINE, EMBASE, and the Cochrane library, including the Cochrane Central Register of Controlled Trials (CENTRAL) until February 2020. Observational studies reporting on the association between Tn and in-hospital and 1-year mortality, and IE complications were considered eligible. As each centre uses different conventional or ultra-sensitive Tn, with different normality threshold, we considered them as normal or elevated according to the criteria specified in each article. Articles were systematically selected, assessed for bias, and, when possible, meta-analysed using a random effect model. After retrieving 542 articles, 18 were included for qualitative synthesis and 9 for quantitative meta-analysis. Compared with patients with normal Tn levels, patients with Tn elevation presented higher in-hospital mortality [odds ratio (OR) 5.96, 95% confidence interval (CI) 3.46–10.26; P < 0.0001], 1-year mortality (OR 2.67, 95% CI 1.42–5.02; P = 0.002), and surgery rates (OR 2.34, 95% CI 1.42–3.85; P = 0.0008). They also suffered more frequent complications: central nervous system events (OR 8.85, 95% CI 3.23–24.26; P < 0.0001) and cardiac abscesses (OR 4.96, 95% CI 1.94–12.70; P = 0.0008).

Conclusion

Tn elevation is associated with a poor prognosis in patients with IE. Troponin determination seems to provide additional help in the prognostic assessment of these patients.
Dispute Settlement in Preferential Trade Agreements and the WTO: A Network Analysis of Idleness and Choice of Forum
Authors: Beyer Vincent
Published: February 2021

It is generally presumed that World Trade Organization (WTO) members display a preference for dispute settlement under WTO rules over those provided for in preferential trade agreements (PTAs). This assumption is driven by observations relating to the large number of PTAs, the low number of PTA cases and the large number of WTO cases, including between PTA partners. These observations are challenged by adopting a methodology that has so far seen relatively limited use in the study of international law network analysis. This article finds, first, the network of connections among WTO members formed by PTAs is far less dense than appears to have been assumed. Second, while almost half of all WTO members have participated in WTO proceedings at least once, the vast majority of bilateral relations among WTO members have never been subject to WTO dispute settlement. This puts the perceived idleness of PTA dispute settlement into perspective. Lastly, the share of WTO cases that could have been settled under PTA procedures is far lower than commonly believed. This low share shows that there is no widespread predilection for the WTO, as commonly argued, but, more often than not, a genuine absence of choice. Ultimately, as the PTA network is unable to act as a substitute, WTO dispute settlement continues to hold a central place in the rules-based global trading system.
The Chlamydomonas Zygospore: Mutant Strains of Chlamydomonas monoica Blocked in Zygospore Morphogenesis Comprise 46 Complementation Groups
Authors: VanWinkle-Swift Karen , Baron Kristin , McNamara Alexander , Minke Peter , Burrascano Cynthia , Maddock Janine
Published: February 2021

Chlamydomonas monoica undergoes homothallic sexual reproduction in response to nitrogen starvation. Mating pairs are established in clonal culture via flagellar agglutination and fuse by way of activated mating structures to form the quadriflagellate zygote. The zygote further matures into a dormant diploid zygospore through a series of events that we collectively refer to as zygosporulation. Mutants that arrest development prior to the completion of zygosporulation have been obtained through the use of a variety of mutagens, including ultraviolet irradiation, 5-fluorodeoxyuridine, ethyl methanesulfonate, and methyl methanesulfonate. Complementation analysis indicates that the present mutant collection includes alleles affecting 46 distinct zygote-specific functions. The frequency with which alleles at previously defined loci have been recovered in the most recent mutant searches suggests that as many as 30 additional zygote-specific loci may still remain to be identified. Nevertheless, the present collection should provide a powerful base for ultrastructural, biochemical, and molecular analysis of zygospore morphogenesis and dormancy in Chlamydomonas.
Multiple Genetic Controls on Rhizobium meliloti syrA, a Regulator of Exopolysaccharide Abundance
Authors: Barnett Melanie J , Swanson Jean A , Long Sharon R
Published: February 2021

Exopolysaccharides (EPS) are produced by a wide assortment of bacteria including plant pathogens and rhizobial symbionts. Rhizobium meliloti mutants defective in EPS production fail to invade alfalfa nodules. Production of EPS in R. meliloti is likely controlled at several levels. We have characterized a new gene of this regulatory circuit. syrA was identified by its ability to confer mucoid colony morphology and by its ability to suppress the colonial phenotype of an exoD mutant. Here we show that syrA encodes a 9-kD hydrophobic protein that has sequence similarity to two other EPS regulatory proteins: ExoX of Rhizobium NGR234 and R. meliloti, and Psi of R. leguminosarum bv. phaseoli. The syrA transcription start site lies 522 nucleotides upstream of a non-canonical TTG start codon. The syrA promoter region is similar to the promoter region of the nodulation regulatory protein, nodD3. We found that in free-living bacteria, syrA expression is activated by the regulatory locus, syrM, but not by nodD3. In planta, syrM is not required for expression of syrA. Instead, expression of the nitrogen fixation (nifHDKE) genes upstream of syrA plays a role. Specific and distinct sets of genetic controls may operate at different times during nodule invasion.
Enhancer of Polycomb Is a Suppressor of Position-Effect Variegation in Drosophila melanogaster
Authors: Sinclair Donald A R , Clegg Nigel J , Antonchuk Jennifer , Milne Thomas A , Stankunas Kryn , Ruse Chris , Grigliatti Thomas A , Kassis Judith A , Brock Hugh W
Published: February 2021

Polycomb group (PcG) genes of Drosophila are negative regulators of homeotic gene expression required for maintenance of determination. Sequence similarity between Polycomb and Su(var)205 led to the suggestion that PcG genes and modifiers of position-effect variegation (PEV) might function analogously in the establishment of chromatin structure. If PcG proteins participate directly in the same process that leads to PEV, PcG mutations should suppress PEV. We show that mutations in E(Pc), an unusual member of the PcG, suppress PEV of four variegating rearrangements: In(l)wm4, BSV, T(2;3)SbV, and In(2R)bwVDe2. Using reversion of a P element insertion, deficiency mapping, and recombination mapping as criteria, homeotic effects and suppression of PEV associated with E(Pc) co-map. Asx is an enhancer of PEV, whereas nine other PcG loci do not affect PEV. These results support the conclusion that there are fewer similarities between PcG genes and modifiers of PEV than previously supposed. However, E(Pc) appears to be an important link between the two groups. We discuss why Asx might act as an enhancer of PEV.
Population Dynamics of the Wolbachia Infection Causing Cytoplasmic Incompatibility in Drosophila melanogaster
Authors: Hoffmann Ary A , Hercus Miriam , Dagher Hayat
Published: February 2021

Field populations of Drosophila melanogaster are often infected with Wolbachia, a vertically transmitted microorganism. Under laboratory conditions the infection causes partial incompatibility in crosses between infected males and uninfected females. Here we examine factors influencing the distribution of the infection in natural populations. We show that the level of incompatibility under field conditions was much weaker than in the laboratory. The infection was not transmitted with complete fidelity under field conditions, while field males did not transmit the infection to uninfected females and Wolbachia did not influence sperm competition. There was no association between field fitness as measured by fluctuating asymmetry and the infection status of adults. Infected field females were smaller than uninfecteds in some collections from a subtropical location, but not in other collections from the same location. Laboratory cage studies showed that the infection did not change in frequency when populations were maintained at a low larval density, but it decreased in frequency at a high larval density. Monitoring of infection frequencies in natural populations indicated stable frequencies in some populations but marked fluctuations in others. Simple models suggest that the infection probably provides a fitness benefit for the host in order to persist in populations. The exact nature of this benefit remains elusive.
The Role of Gene Conversion in Determining Sequence Variation and Divergence in the Est-5 Gene Family in Drosophila pseudoobscura
Authors: King Lynn Mertens
Published: February 2021

Nucleotide sequences of eight Est-5A and Est-5C genes corresponding to previously sequenced Est-5B genes in Drosophila pseudoobscura were determined to compare patterns of polymorphism and divergence among members of this small gene family. The three esterase genes were also sequenced from D. persimilis and D. miranda for interspecific comparisons. The data provide evidence that gene conversion between loci contributes to polymorphism and to the homogenization of the Est-5 genes. For Est-5B, which encodes one of the most highly polymorphic proteins in Drosophila, 12% of the segregating amino acid variants appear to have been introduced via gene conversion from other members of the gene family. Interlocus gene conversion can also explain high sequence similarity, especially at synonymous sites, between Est-5B and Est-5A. Tests of neutrality using interspecific comparisons show that levels of polymorphism conform to neutral expectations at each Est-5 locus. However, McDonald-Kreitman tests based on intraspecific gene comparisons indicate that positive selection on amino acids has accompanied Est-5 gene duplication and divergence in D. pseudoobscura.
An Essential Function of a Phosphoinositide-Specific Phospholipase C Is Relieved by Inhibition of a Cyclin-Dependent Protein Kinase in the Yeast Saccharomyces cerevisiae
Authors: Flick Jeffrey S , Thorner Jeremy
Published: February 2021

The PLC1 gene product of Saccharomyces cerevisiae is a homolog of the δ isoform of mammalian phosphoinositide-specific phospholipase C (PI-PLC). We found that two genes (SPL1 and SPL2), when overexpressed, can bypass the temperature-sensitive growth defect of a plc1Δ cell. SPL1 is identical to the PHO81 gene, which encodes an inhibitor of a cyclin (Pho80p)-dependent protein kinase (Pho85p) complex (Cdk). In addition to overproduction of Pho81p, two other conditions that inactivate this Cdk, a cyclin (pho80Δ) mutation and growth on low-phosphate medium, also permitted growth of plc1Δ cells at the restrictive temperature. Suppression of the temperature sensitivity of plc1Δ cells by pho80Δ does not depend upon the Pho4p transcriptional regulator, the only known substrate of the Pho80p/Pho85p Cdk. The second suppressor, SPL2, encodes a small (17-kD) protein that bears similarity to the ankyrin repeat regions present in Pho81p and in other known Cdk inhibitors. Both pho81Δ and spl2Δ show a synthetic phenotype in combination with plc1Δ. Unlike single mutants, plc1Δ pho81Δ and plc1Δ spl2Δ double mutants were unable to grow on synthetic complete medium, but were able to grow on rich medium.
The Fate of Paternal Mitochondrial DNA in Developing Female Mussels, Mytilus edulis: Implications for the Mechanism of Doubly Uniparental Inheritance of Mitochondrial DNA
Authors: Sutherland Brent , Stewart Donald , Kenchington Ellen R , Zouros Eleftherios
Published: February 2021

Species of the marine mussel family Mytilidae have two types of mitochondrial DNA: one that is transmitted from the mother to both female and male offspring (the F type) and one that is transmitted from the father to sons only (the M type). By using pair matings that produce only female offspring or a mixture of female and male offspring and a pair of oligonucleotide primers that amplify part of the COIII gene of the M but not the F mitochondrial genome, we demonstrate that both male and female embryos receive M mtDNA through the sperm and that within 24 hr after fertilization the M mtDNA is eliminated or is drastically reduced in female embryos but maintained in male embryos. These observations are important for understanding the relationship between mtDNA transmission and sex determination in species with doubly uniparental inheritance of mitochondrial DNA.
An Altered Intron Inhibits Synthesis of the Acetylcholine Receptor α-Subunit in the Paralyzed Zebrafish Mutant nic1
Authors: Sepich Diane S , Wegner Jeremy , O'Shea Sherry , Westerfield Monte
Published: February 2021

The acetylcholine receptor (AChR), an oligomeric protein composed of five subunits, is a component of the postsynaptic membrane at the vertebrate neuromuscular junction that plays a central role in synaptic transmission. The zebrafish mutation nic1 blocks the expression of functional and clustered nicotinic muscle AChRs. To understand the mechanisms underlying this lack of AChRs, we characterized the molecular defect in nic1 mutants. Our results suggest that the mutation affects the gene coding for the α-subunit of the AChR. Southern blot hybridization and DNA sequence analyses showed that the nic1 AChR α-subunit gene lacks part of intron 6 where the splicing branchpoint normally forms. Several lines of evidence suggest that this deletion blocks normal splicing; most nic1 α-subunit mRNAs retain intron 6 and are larger and less abundant than wild-type, some nic1 α-subunit mRNAs are internally deleted, and wild-type α-subunit mRNA rescues nic1 mutant cells. The nic1 mutation reduces the size of an intron, which prevents efficient splicing of the pre-mRNA, thus blocking synthesis of the α-subunit and assembly of AChRs. By this route, the nic1 mutation leads to paralysis.
A High-Density Rice Genetic Linkage Map with 2275 Markers Using a Single F2 Population
Authors: Harushima Yoshiaki , Yano Masahiro , Shomura Ayahiko , Sato Mikiko , Shimano Tomotoshi , Kuboki Yoshihide , Yamamoto Toshio , Lin Shao Yang , Antonio Baltazar A , Parco Arnold , Kajiya Hiromi , Huang Ning , Yamamoto Kimiko , Nagamura Yoshiaki , Kurata Nori , Khush Gurdev S , Sasaki Takuji
Published: February 2021

A 2275-marker genetic map of rice (Oryza sativa L.) covering 1521.6 cM in the Kosambi function has been constructed using 186 F2 plants from a single cross between the japonica variety Nipponbare and the indica variety Kasalath. The map provides the most detailed and informative genetic map of any plant. Centromere locations on 12 linkage groups were determined by dosage analysis of secondary and telotrisomics using >130 DNA markers located on respective chromosome arms. A limited influence on meiotic recombination inhibition by the centromere in the genetic map was discussed. The main sources of the markers in this map were expressed sequence tag (EST) clones from Nipponbare callus, root, and shoot libraries. We mapped 1455 loci using ESTs; 615 of these loci showed significant similarities to known genes, including single-copy genes, family genes, and isozyme genes. The high-resolution genetic map permitted us to characterize meiotic recombinations in the whole genome. Positive interference of meiotic recombination was detected both by the distribution of recombination number per each chromosome and by the distribution of double crossover interval lengths.
Least Squares Interval Mapping of Quantitative Trait Loci Under the Infinitesimal Genetic Model in Outbred Populations
Authors: Liu Z , Dekkers J C M
Published: February 2021

Genetic marker and phenotypic data for a quantitative trait were simulated on 20 paternal half-sib families with 100 progeny to investigate properties of within-family-regression interval mapping of a postulated single quantitative trait locus (QTL) in a marker interval under the infinitesimal genetic model, which has been the basis of the application of quantitative genetics to genetic improvement programs, and to investigate use of the infinitesimal model as null hypothesis in testing for presence of a major QTL. Genetic effects on the marked chromosome were generated based on a major gene model, which simulated a central biallelic QTL, or based on 101 biallelic QTL of equal effect, which approximated the infinitesimal model. The marked chromosome contained 0, 3.3%, 13.3%, or 33.3% of genetic variance and heritability was 0.25 or 0.70. Under the polygenic model with 3.3% of genetic variance on the marked chromosome, which corresponds to the infinitesimal model for the bovine, significant QTL effects were found for individual families. Correlations between estimates of QTL effects and true chromosome substitution effects were 0.29 and 0.47 for heritabilities of 0.25 and 0.70 but up to 0.85 with 33.3% of polygenic variance on the marked chromosome. These results illustrate the potential of marker-assisted selection even under the infinitesimal genetic model. Power of tests for presence of QTL was substantially reduced when the polygenic model with 3.3% of genetic variance on the chromosome was used as a null hypothesis. The ability to determine whether genetic variance on a chromosome was contributed by a single QTL of major effect or a large number of QTL with minor effects, corresponding to the infinitesimal model, was limited.
Evidence for Independent Mismatch Repair Processing on Opposite Sides of a Double-Strand Break in Saccharomyces cerevisiae
Authors: Weng Yi-shin , Nickoloff Jac A
Published: February 2021

Double-strand break (DSB) induced gene conversion in Saccharomyces cerevisiae during meiosis and MAT switching is mediated primarily by mismatch repair of heteroduplex DNA (hDNA). We used nontandem ura3 duplications containing palindromic frameshift insertion mutations near an HO nuclease recognition site to test whether mismatch repair also mediates DSB-induced mitotic gene conversion at a non-MAT locus. Palindromic insertions included in hDNA are expected to produce a stem-loop mismatch, escape repair, and segregate to produce a sectored (Ura+/−) colony. If conversion occurs by gap repair, the insertion should be removed on both strands, and converted colonies will not be sectored. For both a 14-bp palindrome, and a 37-bp near-palindrome, ~75% of recombinant colonies were sectored, indicating that most DSB-induced mitotic gene conversion involves mismatch repair of hDNA. We also investigated mismatch repair of well-repaired markers flanking an unrepaired palindrome. As seen in previous studies, these additional markers increased loop repair (likely reflecting corepair). Among sectored products, few had additional segregating markers, indicating that the lack of repair at one marker is not associated with inefficient repair at nearby markers. Clear evidence was obtained for low levels of short tract mismatch repair. As seen with full gene conversions, donor alleles in sectored products were not altered. Markers on the same side of the DSB as the palindrome were involved in hDNA less often among sectored products than nonsectored products, but markers on the opposite side of the DSB showed similar hDNA involvement among both product classes. These results can be explained in terms of corepair, and they suggest that mismatch repair on opposite sides of a DSB involves distinct repair tracts.
TOR2 Is Part of Two Related Signaling Pathways Coordinating Cell Growth in Saccharomyces cerevisiae
Authors: Helliwell Stephen B , Howald Isabelle , Barbet Nik , Hall Michael N
Published: February 2021

The Saccharomyces cerevisiae genes TOR1 and TOR2 encode phosphatidylinositol kinase homologs. TOR2 has two essential functions. One function overlaps with TOR1 and mediates protein synthesis and cell cycle progression. The second essential function of TOR2 is unique to TOR2 and mediates the cell-cycle-dependent organization of the actin cytoskeleton. We have isolated temperature-sensitive mutants that are defective for either one or both of the two TOR2 functions. The three classes of mutants were as follows. Class A mutants, lacking only the TOR2-unique function, are defective in actin cytoskeleton organization and arrest within two to three generations as small-budded cells in the G2/M phase of the cell cycle. Class B mutants, lacking only the TOR-shared function, and class C mutants, lacking both functions, exhibit a rapid loss of protein synthesis and a G1 arrest within one generation. To define further the two functions of TOR2, we isolated multicopy suppressors that rescue the class A or B mutants. Overexpression of MSS4, PKC1, PLC1, RHO2, ROM2, or SUR1 suppressed the growth defect of a class A mutant. Surprisingly, overexpression of PLC1 and MSS4 also suppressed the growth defect of a class B mutant. These genes encode proteins that are involved in phosphoinositide metabolism and signaling. Thus, the two functions (readouts) of TOR2 appear to involve two related signaling pathways controlling cell growth.
Organization of Chromosome Ends in Ustilago maydis. RecQ-like Helicase Motifs at Telomeric Regions
Authors: Sánchez-Alonso Patricia , Guzmán Plinio
Published: February 2021

In this study we have established the structure of chromosome ends in the basidiomycete fungus Ustilago maydis. We isolated and characterized several clones containing telomeric regions and found that as in other organisms, they consist of middle repeated DNA sequences. Two principal types of sequence were found: UTASa was highly conserved in nucleotide sequence and located almost exclusively at the chromosome ends, and UTASb was less conserved in nucleotide sequence than UTASa and found not just at the ends but highly interspersed throughout the genome. Sequence analysis revealed that UTASa encodes an open reading frame containing helicase motifs with the strongest homology to RecQ helicases; these are DNA helicases whose function involves the maintenance of genome stability in Saccharomyces cerevisiae and in humans, and the suppression of illegitimate recombination in Escherichia coli. Both UTASa and UTASb contain a common region of about 300 bp located immediately adjacent to the telomere repeats that are also found interspersed in the genome. The analysis of the chromosome ends of U. maydis provides information on the general structure of chromosome ends in eukaryotes, and the putative RecQ helicase at UTASa may reveal a novel mechanism for the maintenance of chromosome stability.
Genetic Analysis of the Drosophila αPS2 Integrin Subunit Reveals Discrete Adhesive, Morphogenetic and Sarcomeric Functions
Authors: Bloor James W , Brown Nicholas H
Published: February 2021

The integrin family of cell surface receptors mediates cell-substrate and cell-to-cell adhesion and transmits intracellular signals. In Drosophila there is good evidence for an adhesive role of integrins, but evidence for integrin signalling has remained elusive. Each integrin is an αβ heterodimer, and the Drosophila βPS subunit forms at least two integrins by association with different α subunits: αPS1βPS (PS1) and αPS2βPS (PS2). The complex pattern of PS2 integrin expression includes, but is more extensive than, the sites where PS2 has a known requirement. In order to investigate whether PS2 integrin is required at these additional sites and/or has functions besides mediating adhesion, a comprehensive genetic analysis of inflated, the gene that encodes αPS2, was performed. We isolated 35 new inflated alleles, and obtained 10 alleles from our colleagues. The majority of alleles are amorphs (36/45) or hypomorphs (4/45), but five alleles that affect specific developmental processes were identified. Interallelic complementation between these alleles suggests that some may affect distinct functional domains of the αPS2 protein, which specify particular interactions that promote adhesion or signalling. One new allele reveals that the PS2 integrin is required for the development of the adult halteres and legs as well as the wing.
Genetic Analysis of Drosophila Larval Optic Nerve Development
Authors: Holmes Amy L , Raper R Nathan , Heilig Joseph S
Published: February 2021

To identify genes necessary for establishing connections in the Drosophila sensory nervous system, we designed a screen for mutations affecting development of the larval visual system. The larval visual system has a simple and stereotypic morphology, can be recognized histologically by a variety of techniques, and is unnecessary for viability. Therefore, it provides an opportunity to identify genes involved in all stages of development of a simple, specific neuronal connection. By direct observation of the larval visual system in mutant embryos, we identified 24 mutations affecting its development; 13 of these are larval visual system-specific. These 13 mutations can be grouped phenotypically into five classes based on their effects on location, path or morphology of the larval visual system nerves and organs. These mutants and phenotypic classifications provide a context for further analysis of neuronal development, pathfinding and target recognition.
Quantitative Trait Loci for Honey Bee Stinging Behavior and Body Size
Authors: Hunt Greg J , Guzmán-Novoa Ernesto , Fondrk M Kim , Page Robert E
Published: February 2021

A study was conducted to identify quantitative trait loci (QTLs) that affect colony-level stinging behavior and individual body size of honey bees. An F1 queen was produced from a cross between a queen of European origin and a drone descended from an African subspecies. Haploid drones from the hybrid queen were individually backcrossed to sister European queens to produce 172 colonies with backcross workers that were evaluated for tendency to sting. Random amplified polymorphic DNA markers were scored from the haploid drone fathers of these colonies. Wings of workers and drones were used as a measure of body size because Africanized bees in the Americas are smaller than European bees. Standard interval mapping and multiple QTL models were used to analyze data. One possible QTL was identified with a significant effect on tendency to sting (LOD 3.57). Four other suggestive QTLs were also observed (about LOD 1.5). Possible QTLs also were identified that affect body size and were unlinked to defensive-behavior QTLs. Two of these were significant (LOD 3.54 and 5.15).
Genetic Response from Marker Assisted Selection in an Outbred Population for Differing Marker Bracket Sizes and with Two Identified Quantitative Trait Loci
Authors: Spelman Richard , Bovenhuis Henk
Published: February 2021

Effect of flanking quantitative trait loci (QTL)-marker bracket size on genetic response to marker assisted selection in an outbred population was studied by simulation of a nucleus breeding scheme. In addition, genetic response with marker assisted selection (MAS) from two quantitative trait loci on the same and different chromosome(s) was investigated. QTL that explained either 5% or 10% of phenotypic variance were simulated. A polygenic component was simulated in addition to the quantitative trait loci. In total, 35% of the phenotypic variance was due to genetic factors. The trait was measured on females only. Having smaller marker brackets flanking the QTL increased the genetic response from MAS selection. This was due to the greater ability to trace the QTL transmission from one generation to the next with the smaller flanking QTL-marker bracket, which increased the accuracy of estimation of the QTL allelic effects. Greater negative covariance between effects at both QTL was observed when two QTL were located on the same chromosome compared to different chromosomes. Genetic response with MAS was greater when the QTL were on the same chromosome in the early generations and greater when they were on different chromosomes in the later generations of MAS.
Likelihood Models for Detecting Positively Selected Amino Acid Sites and Applications to the HIV-1 Envelope Gene
Authors: Nielsen Rasmus , Yang Ziheng
Published: February 2021

Several codon-based models for the evolution of protein-coding DNA sequences are developed that account for varying selection intensity among amino acid sites. The “neutral model” assumes two categories of sites at which amino acid replacements are either neutral or deleterious. The “positive-selection model” assumes an additional category of positively selected sites at which nonsynonymous substitutions occur at a higher rate than synonymous ones. This model is also used to identify target sites for positive selection. The models are applied to a data set of the V3 region of the HIV-1 envelope gene, sequenced at different years after the infection of one patient. The results provide strong support for variable selection intensity among amino acid sites The neutral model is rejected in favor of the positive-selection model, indicating the operation of positive selection in the region. Positively selected sites are found in both the V3 region and the flanking regions.
The Chromosome Bias of Misincorporations During Double-Strand Break Repair Is Not Altered in Mismatch Repair–Defective Strains of Saccharomyces cerevisiae
Authors: McGill Carolyn B , Holbeck Susan L , Strathern Jeffrey N
Published: February 2021

Recombinational repair of a site-specific, double-strand DNA break (DSB) results in increased reversion frequency for nearby mutations. Although some models for DSB repair predict that newly synthesized DNA will be inherited equally by both the originally broken chromosome and the chromosome that served as a template, the DNA synthesis errors are almost exclusively found on the chromosome that had the original DSB (introduced by the HO endonuclease). To determine whether mismatch repair acts on the template chromosome in a directed fashion to restore mismatches to the initial sequence, these experiments were repeated in mismatch repair-defective (pms1, mlh1, and msh2) backgrounds. The results suggest that mismatch repair is not responsible for the observed bias.
Differential Response of Mouse Male Germ-Cell Stages to Radiation-Induced Specific-Locus and Dominant Mutations
Authors: Russell W L , Bangham Jean W , Russell Liane B
Published: February 2021

In an attempt to provide a systematic assessment of the frequency and nature of mutations induced in successive stages of spermato- and spermiogenesis, X-irradiated male mice were re-mated at weekly intervals, and large samples of progeny, observed from birth onward, were scored and genetically tested for recessive mutations at seven specific loci and for externally recognizable dominant mutations. Productivity findings provided a rough measure of induced dominant-lethal frequencies. A qualitative assessment of specific-locus mutations (which include deletions and other rearrangements) was made on the basis of homozygosity test results, as well as from information derived from more recent complementation studies and molecular analyses. Both recessive and dominant visibles revealed clear distinctions between spermatogonia and postspermatogonial stages. In addition, differences for both of these endpoints, as well as for presumed dominant lethals, were found among various postspermatogonial stages. It may be concluded that radiation produces its maximum rates of genetic damage in germ-cell stages ranging from midpachytene spermatocytes through early spermatids, a pattern unlike any of those that have been defined for chemicals; further, the frequency peaks for radiation are lower and broader. The difference between post-stem-cell stages overall and stem-cell spermatogonia was smaller than is generally found with chemicals, not only with respect to the frequency but also the nature of mutations.
The Spectrum of Acridine Resistant Mutants of Bacteriophage T4 Reveals Cryptic Effects of the tsL141 DNA Polymerase Allele on Spontaneous Mutagenesis
Authors: Wang Fei Jun , Ripley Lynn S
Published: February 2021

Mutations in the ac gene of bacteriophage T4 confer resistance to acridine-inhibition of phage development. Previous studies had localized the ac gene region; we show that inactivation of T4 Open Reading Frame 52.2 confers the Acr phenotype. Thus, 52.2 is ac. The resistance mechanism is unknown. The ac gene provides a convenient forward mutagenesis assay. Its compact size (156 bp) simplifies mutant sequencing and diverse mutant types are found: base substitutions leading to missense or nonsense codons, inframe deletions or duplications within the coding sequence, deletion or duplication frameshifts, insertions, complex mutations, and large deletions extending into neighboring sequences. Comparisons of spontaneous mutagenesis between phages bearing the wild-type or tsL141 alleles of DNA polymerase demonstrate that the impact of the mutant polymerase is cryptic when total spontaneous mutant frequencies are compared, but the DNA sequences of the ac mutants reveal a substantial alteration of fidelity by the mutant polymerase. The patterns of base substitution mutagenesis suggest that some site-specific mutation rate effects may reflect hotspots for mutagenesis arising by different mechanisms. A new class of spontaneous duplication mutations, having sequences inconsistent with misaligned pairing models, but consistent with nick-processing errors, has been identified at a hotspot in ac.
Rates of Spontaneous Mutation
Authors: Drake John W , Charlesworth Brian , Charlesworth Deborah , Crow James F
Published: February 2021

Rates of spontaneous mutation per genome as measured in the laboratory are remarkably similar within broad groups of organisms but differ strikingly among groups. Mutation rates in RNA viruses, whose genomes contain ca. 104 bases, are roughly 1 per genome per replication for lytic viruses and roughly 0.1 per genome per replication for retroviruses and a retrotransposon. Mutation rates in microbes with DNA-based chromosomes are close to 1/300 per genome per replication; in this group, therefore, rates per base pair vary inversely and hugely as genome sizes vary from 6 × 103 to 4 × 107 bases or base pairs. Mutation rates in higher eukaryotes are roughly 0.1–100 per genome per sexual generation but are currently indistinguishable from 1/300 per cell division per effective genome (which excludes the fraction of the genome in which most mutations are neutral). It is now possible to specify some of the evolutionary forces that shape these diverse mutation rates.
Identification and Characterization of an Essential Family of Inositol Polyphosphate 5-Phosphatases (INP51, INP52 and INP53 Gene Products) in the Yeast Saccharomyces cerevisiae
Authors: Stolz Leslie E , Huynh Chau V , Thorner Jeremy , York John D
Published: February 2021

We recently demonstrated that the S. cerevisiae INP51 locus (YIL002c) encodes an inositol polyphosphate 5-phosphatase. Here we describe two related yeast loci, INP52 (YNL106c) and INP53 (YOR109w). Like Inp51p, the primary structures of Inp52p and Inp53p resemble the mammalian synaptic vesicle-associated protein, synaptojanin, and contain a carboxy-terminal catalytic domain and an amino-terminal SAC1-like segment. Inp51p (108 kD), Inp52p (136 kD) and Inp53p (124 kD) are membrane-associated. Single null mutants (inp51, inp52, or inp53) are viable. Both inp51 inp52 and inp52 inp53 double mutants display compromised cell growth, whereas an inp51 inp53 double mutant does not. An inp51 inp52 inp53 triple mutant is inviable on standard medium, but can grow weakly on media supplemented with an osmotic stabilizer (1 M sorbitol). An inp51 mutation, and to a lesser degree an inp52 mutation, confers cold-resistant growth in a strain background that cannot grow at temperatures below 15°. Analysis of inositol metabolites in vivo showed measurable accumulation of phosphatidylinositol 4,5-bisphosphate in the inp51 mutant. Electron microscopy revealed plasma membrane invaginations and cell wall thickening in double mutants and the triple mutant grown in sorbitol-containing medium. A fluorescent dye that detects endocytic and vacuolar membranes suggests that the vacuole is highly fragmented in inp51 inp52 double mutants. Our observations indicate that Inp51p, Inp52p, and Inp53p have distinct functions and that substrates and/or products of inositol polyphosphate 5-phosphatases may have roles in vesicle trafficking, membrane structure, and/or cell wall formation.