How to dissect the pelvic nerves: from microanatomy to surgical rules. An evidence-based clinical review.

Background: Advanced gynaecological procedures often include extensive pelvic dissections, with the nervous structures involved in the disease. Nerve-sparing and preservation is a key factor in reducing postoperative morbidity. Objectives: The goal of this review is to describe in detail the structure of the pelvic nerves and to gather information from other surgical specialties to give recommendations for safe nerve dissection applied in different gynaecological subspecialties. Materials and Methods: An extensive literature review was carried out in PubMed and Google Scholar. The search included articles concerning peripheral nerve anatomy, mechanisms of injury and different dissection techniques, with the most exhaustive being analysed for the review. Articles from different fields of medicine like orthopaedics, plastic surgery, maxillofacial surgery dealing with peripheral nerve injuries and repair have been reviewed. Results: The following review demonstrates the in-depth anatomy and mechanism of injury of the peripheral nerves, describes the different techniques for neurolysis and proposes some directions for safe nerve dissection. Conclusion: When performing complex gynaecological surgeries, the surgeon should avoid unnecessary nerve handling, apply nerve-sparing techniques whenever possible and use the new devices to preserve the nervous structures. Advanced gynaecological surgeries should be performed in specialised centres by expert surgeons with comprehensive knowledge in neuropelveology. What is new?: To our knowledge, this is the first article focused on peripheral nerves that collects data from such a wide range of specialties in order to propose the most comprehensive recommendations that could be applied in pelvic surgery.

Mesh-less laparoscopic treatment of apical prolapse.

The pelvic organ prolapse (POP) is a common gynaecological problem, affecting nearly 50% of women over 40. The sacrocolpopexy using a synthetic mesh is now considered the "gold standard" for management of women with apical prolapse. In April 2019 the FDA placed a ban on the production of transvaginal meshes for prolapse due to late complications. The meshes for abdominal repair of POP are still used, but in future they may also be prohibited. The goal of the following video is to present a mesh-less modification of two techniques used for apical organ prolapse, the sacrocolpopexy and the pectopexy.

Genome-wide meta-analysis of variant-by-diuretic interactions as modulators of lipid traits in persons of European and African ancestry.

Hypertension (HTN) is a significant risk factor for cardiovascular morbidity and mortality. Metabolic abnormalities, including adverse cholesterol and triglycerides (TG) profiles, are frequent comorbid findings with HTN and contribute to cardiovascular disease. Diuretics, which are used to treat HTN and heart failure, have been associated with worsening of fasting lipid concentrations. Genome-wide meta-analyses with 39,710 European-ancestry (EA) individuals and 9925 African-ancestry (AA) individuals were performed to identify genetic variants that modify the effect of loop or thiazide diuretic use on blood lipid concentrations. Both longitudinal and cross sectional data were used to compute cohort-specific interaction results, which were then combined through meta-analysis in each ancestry. These ancestry-specific results were further combined through trans-ancestry meta-analysis. Analysis of EA data identified two genome-wide significant (p < 5 × 10-8) loci with single nucleotide variant (SNV)-loop diuretic interaction on TG concentrations (including COL11A1). Analysis of AA data identified one genome-wide significant locus adjacent to BMP2 with SNV-loop diuretic interaction on TG concentrations. Trans-ancestry analysis strengthened evidence of association for SNV-loop diuretic interaction at two loci (KIAA1217 and BAALC). There were few significant SNV-thiazide diuretic interaction associations on TG concentrations and for either diuretic on cholesterol concentrations. Several promising loci were identified that may implicate biologic pathways that contribute to adverse metabolic side effects from diuretic therapy.

Large-scale pharmacogenomic study of sulfonylureas and the QT, JT and QRS intervals: CHARGE Pharmacogenomics Working Group.

Sulfonylureas, a commonly used class of medication used to treat type 2 diabetes, have been associated with an increased risk of cardiovascular disease. Their effects on QT interval duration and related electrocardiographic phenotypes are potential mechanisms for this adverse effect. In 11 ethnically diverse cohorts that included 71 857 European, African-American and Hispanic/Latino ancestry individuals with repeated measures of medication use and electrocardiogram (ECG) measurements, we conducted a pharmacogenomic genome-wide association study of sulfonylurea use and three ECG phenotypes: QT, JT and QRS intervals. In ancestry-specific meta-analyses, eight novel pharmacogenomic loci met the threshold for genome-wide significance (P<5 × 10-8), and a pharmacokinetic variant in CYP2C9 (rs1057910) that has been associated with sulfonylurea-related treatment effects and other adverse drug reactions in previous studies was replicated. Additional research is needed to replicate the novel findings and to understand their biological basis.

A novel Alzheimer disease locus located near the gene encoding tau protein.

APOE ɛ4, the most significant genetic risk factor for Alzheimer disease (AD), may mask effects of other loci. We re-analyzed genome-wide association study (GWAS) data from the International Genomics of Alzheimer's Project (IGAP) Consortium in APOE ɛ4+ (10 352 cases and 9207 controls) and APOE ɛ4- (7184 cases and 26 968 controls) subgroups as well as in the total sample testing for interaction between a single-nucleotide polymorphism (SNP) and APOE ɛ4 status. Suggestive associations (P<1 × 10(-4)) in stage 1 were evaluated in an independent sample (stage 2) containing 4203 subjects (APOE ɛ4+: 1250 cases and 536 controls; APOE ɛ4-: 718 cases and 1699 controls). Among APOE ɛ4- subjects, novel genome-wide significant (GWS) association was observed with 17 SNPs (all between KANSL1 and LRRC37A on chromosome 17 near MAPT) in a meta-analysis of the stage 1 and stage 2 data sets (best SNP, rs2732703, P=5·8 × 10(-9)). Conditional analysis revealed that rs2732703 accounted for association signals in the entire 100-kilobase region that includes MAPT. Except for previously identified AD loci showing stronger association in APOE ɛ4+ subjects (CR1 and CLU) or APOE ɛ4- subjects (MS4A6A/MS4A4A/MS4A6E), no other SNPs were significantly associated with AD in a specific APOE genotype subgroup. In addition, the finding in the stage 1 sample that AD risk is significantly influenced by the interaction of APOE with rs1595014 in TMEM106B (P=1·6 × 10(-7)) is noteworthy, because TMEM106B variants have previously been associated with risk of frontotemporal dementia. Expression quantitative trait locus analysis revealed that rs113986870, one of the GWS SNPs near rs2732703, is significantly associated with four KANSL1 probes that target transcription of the first translated exon and an untranslated exon in hippocampus (P ⩽ 1.3 × 10(-8)), frontal cortex (P ⩽ 1.3 × 10(-9)) and temporal cortex (P⩽1.2 × 10(-11)). Rs113986870 is also strongly associated with a MAPT probe that targets transcription of alternatively spliced exon 3 in frontal cortex (P=9.2 × 10(-6)) and temporal cortex (P=2.6 × 10(-6)). Our APOE-stratified GWAS is the first to show GWS association for AD with SNPs in the chromosome 17q21.31 region. Replication of this finding in independent samples is needed to verify that SNPs in this region have significantly stronger effects on AD risk in persons lacking APOE ɛ4 compared with persons carrying this allele, and if this is found to hold, further examination of this region and studies aimed at deciphering the mechanism(s) are warranted.

GWAS for executive function and processing speed suggests involvement of the CADM2 gene.

To identify common variants contributing to normal variation in two specific domains of cognitive functioning, we conducted a genome-wide association study (GWAS) of executive functioning and information processing speed in non-demented older adults from the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium. Neuropsychological testing was available for 5429-32,070 subjects of European ancestry aged 45 years or older, free of dementia and clinical stroke at the time of cognitive testing from 20 cohorts in the discovery phase. We analyzed performance on the Trail Making Test parts A and B, the Letter Digit Substitution Test (LDST), the Digit Symbol Substitution Task (DSST), semantic and phonemic fluency tests, and the Stroop Color and Word Test. Replication was sought in 1311-21860 subjects from 20 independent cohorts. A significant association was observed in the discovery cohorts for the single-nucleotide polymorphism (SNP) rs17518584 (discovery P-value=3.12 × 10(-8)) and in the joint discovery and replication meta-analysis (P-value=3.28 × 10(-9) after adjustment for age, gender and education) in an intron of the gene cell adhesion molecule 2 (CADM2) for performance on the LDST/DSST. Rs17518584 is located about 170 kb upstream of the transcription start site of the major transcript for the CADM2 gene, but is within an intron of a variant transcript that includes an alternative first exon. The variant is associated with expression of CADM2 in the cingulate cortex (P-value=4 × 10(-4)). The protein encoded by CADM2 is involved in glutamate signaling (P-value=7.22 × 10(-15)), gamma-aminobutyric acid (GABA) transport (P-value=1.36 × 10(-11)) and neuron cell-cell adhesion (P-value=1.48 × 10(-13)). Our findings suggest that genetic variation in the CADM2 gene is associated with individual differences in information processing speed.

Is the adiposity-associated FTO gene variant related to all-cause mortality independent of adiposity? Meta-analysis of data from 169,551 Caucasian adults.

Previously, a single nucleotide polymorphism (SNP), rs9939609, in the FTO gene showed a much stronger association with all-cause mortality than expected from its association with body mass index (BMI), body fat mass index (FMI) and waist circumference (WC). This finding implies that the SNP has strong pleiotropic effects on adiposity and adiposity-independent pathological pathways that leads to increased mortality. To investigate this further, we conducted a meta-analysis of similar data from 34 longitudinal studies including 169,551 adult Caucasians among whom 27,100 died during follow-up. Linear regression showed that the minor allele of the FTO SNP was associated with greater BMI (n = 169,551; 0.32 kg m(-2) ; 95% CI 0.28-0.32, P < 1 × 10(-32) ), WC (n = 152,631; 0.76 cm; 0.68-0.84, P < 1 × 10(-32) ) and FMI (n = 48,192; 0.17 kg m(-2) ; 0.13-0.22, P = 1.0 × 10(-13) ). Cox proportional hazard regression analyses for mortality showed that the hazards ratio (HR) for the minor allele of the FTO SNPs was 1.02 (1.00-1.04, P = 0.097), but the apparent excess risk was eliminated after adjustment for BMI and WC (HR: 1.00; 0.98-1.03, P = 0.662) and for FMI (HR: 1.00; 0.96-1.04, P = 0.932). In conclusion, this study does not support that the FTO SNP is associated with all-cause mortality independently of the adiposity phenotypes.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Meta-analysis of 74,046 individuals identifies 11 new susceptibility loci for Alzheimer's disease.

Eleven susceptibility loci for late-onset Alzheimer's disease (LOAD) were identified by previous studies; however, a large portion of the genetic risk for this disease remains unexplained. We conducted a large, two-stage meta-analysis of genome-wide association studies (GWAS) in individuals of European ancestry. In stage 1, we used genotyped and imputed data (7,055,881 SNPs) to perform meta-analysis on 4 previously published GWAS data sets consisting of 17,008 Alzheimer's disease cases and 37,154 controls. In stage 2, 11,632 SNPs were genotyped and tested for association in an independent set of 8,572 Alzheimer's disease cases and 11,312 controls. In addition to the APOE locus (encoding apolipoprotein E), 19 loci reached genome-wide significance (P < 5 × 10(-8)) in the combined stage 1 and stage 2 analysis, of which 11 are newly associated with Alzheimer's disease.

Association of heat shock proteins with all-cause mortality.

Experimental mild heat shock is widely known as an intervention that results in extended longevity in various models along the evolutionary lineage. Heat shock proteins (HSPs) are highly upregulated immediately after a heat shock. The elevation in HSP levels was shown to inhibit stress-mediated cell death, and recent experiments indicate a highly versatile role for these proteins as inhibitors of programmed cell death. In this study, we examined common genetic variations in 31 genes encoding all members of the HSP70, small HSP, and heat shock factor (HSF) families for their association with all-cause mortality. Our discovery cohort was the Rotterdam study (RS1) containing 5,974 participants aged 55 years and older (3,174 deaths). We assessed 4,430 single nucleotide polymorphisms (SNPs) using the HumanHap550K Genotyping BeadChip from Illumina. After adjusting for multiple testing by permutation analysis, three SNPs showed evidence for association with all-cause mortality in RS1. These findings were followed in eight independent population-based cohorts, leading to a total of 25,007 participants (8,444 deaths). In the replication phase, only HSF2 (rs1416733) remained significantly associated with all-cause mortality. Rs1416733 is a known cis-eQTL for HSF2. Our findings suggest a role of HSF2 in all-cause mortality.

The interaction of adiposity with the CRP gene affects CRP levels: age, gene/environment susceptibilty-Reykjavik study.

OBJECTIVE: Common diseases often have an inflammatory component reflected by associated markers such as serum C-reactive protein (CRP) levels. Circulating CRP levels have also been associated with adipose tissue as well as with specific CRP genotypes. We examined the interaction between measures of body mass index (BMI), waist circumference and fat percent (total fat measured by bioimpedance) with genotypes of the CRP gene in the determination of CRP levels. METHODS: The first 2296 participants (mean age 76+/-6 years, 42% men) in the Age, Gene/Environment Susceptibility-Reykjavik Study, a multidisciplinary epidemiological study to determine risk factors in aging, were genotyped for 10 single nucleotide polymorphisms (SNPs) in the CRP gene. General linear models with age and terms for interaction of CRP genotypes with BMI, waist circumference and percent fat were used to evaluate the association of genotypes to CRP levels (high-sensitivity method, range 0-10 mg l(-1)) in men and women separately. RESULTS: We focused on the SNP rs1205 that represents the allele that captures the strongest effects of the gene on CRP levels. Carriers of the rs1205 G allele had significantly higher CRP levels than noncarriers in a dose-dependent manner. Compared to the AA genotype, the slope of the increase in CRP with increasing BMI (P=0.045) and waist circumference (P=0.014) was different for the G allele carriers and of similar magnitude in both men and women. The rs1205 interactions were not significant for fat mass percent, suggesting a possible association with fat localization. CONCLUSIONS: This study further illuminates the known association between measures of adiposity and CRP levels and is shown to be dependent on variation in the rs1205 SNP of the CRP gene. The correlated increase in CRP levels with adiposity is accentuated by presence of the G allele.

90% pump depletion and good beam quality in a pulse-injection-seeded nanosecond optical parametric oscillator.

We measured 90% pump depletion in a singly resonant image-rotating nanosecond optical parametric oscillator that was pulse-injection seeded by a self-generated signal pulse. The oscillator was pumped by an 8 ns duration single-frequency 532 nm pulse from an injection-seeded Q-switched Nd:YAG laser and resonated an 803 nm signal. The pump and pulsed-seed beams had flat-topped spatial fluence profiles with diameters of approximately 6 mm, giving a cavity Fresnel number at 803 nm approaching 400. The beam cleanup effects of the image-rotating cavity produce a far-field signal spatial fluence profile with approximately 60% of its energy falling within the diffraction-limited spot size.

Influence of cranberry juice on glucan-mediated processes involved in Streptococcus mutans biofilm development.

Cranberry juice (CJ) has biological properties that may provide health benefits. In this study, we investigated the influence of CJ (pH 5.5) on several activities in vitro associated with the development of Streptococcus mutans UA159 biofilms. The ability of CJ to influence the adherence of S. mutans to either saliva- (sHA) or glucan-coated hydroxyapatite (gsHA), and to inhibit the glucan production by purified glucosyltransferases adsorbed to sHA was determined. For the adherence assays, we used both uncoated and saliva-coated bacterial cells. Furthermore, we examined whether CJ interferes with the viability, development, polysaccharide composition and acidogenicity of S. mutans biofilms. A solution containing equivalent amounts of glucose, fructose and organic acids at pH 5.5 was used as negative control. The adherence of S. mutans (uncoated and saliva-coated) to either sHA or gsHA treated with 25% CJ (v/v) was remarkably reduced (40-85% inhibition compared to control: p < 0.05), indicating that CJ effectively blocked the bacterial adherence to binding sites in salivary pellicle and in glucans. In contrast, when the bacterial cells alone were treated with CJ they adhered to the similar untreated surfaces. Cranberry juice (25%, v/v) also inhibited the activities of surface-adsorbed GTF B and C (70-80% inhibition compared to control, p < 0.05). The effect of CJ on the viability of microorganisms in biofilms was not significant. Biofilm formation and accumulation were significantly reduced by topical applications of 25% CJ (v/v) twice daily with 1-min exposures (p < 0.05). The biomass and insoluble glucan content of the biofilms in addition to its acidogenicity were significantly reduced by cranberry treatments (p < 0.05). Our data show that cranberry juice inhibited glucan-mediated biofilm development and acid production, and holds promise as a natural product to prevent biofilm-related oral diseases.

Protein refolding versus aggregation: computer simulations on an intermediate-resolution protein model.

Computer simulations are performed on a system of eight model peptide chains to study how the competition between protein refolding and aggregation affects the optimal conditions for refolding of four-helix bundles. The discontinuous molecular dynamics algorithm is utilized along with an intermediate-resolution protein model that we developed for this work. Physically, the model is much more detailed than any model used to date for simulations of protein aggregation. Each model residue consists of a detailed, three-bead backbone and a simplified, single-bead side-chain. Excluded volume, hydrogen bond, and hydrophobic interactions are modeled with discontinuous (i.e. hard-sphere and square-well) potentials. Simulations efficiently sample conformational space, and complete folding trajectories from random initial configurations to two four-helix bundles are possible within two days on a single processor workstation. Folding of the bundles follows two main pathways, one through a trimeric intermediate and the other through an intermediate with two dimers. The proportion of trajectories that follow each route is significantly different for the eight-peptide system in this work than in a previously studied four-peptide system, which yields one four-helix bundle, suggesting, as our previous simulations have, that protein folding properties are strongly influenced by the presence of other proteins. Folding of the bundles is optimal within a fixed temperature range, with the high-temperature boundary a function of the complexity of the protein (or oligomer) to be folded and the low-temperature boundary a function of the complexity of the protein's environment. Above the optimal temperature range for folding, the model chains tend to unfold; below the optimal range, the model chains tend to aggregate. As has been seen previously, aggregates have substantial levels of native secondary structure, suggesting that aggregates are composed largely of partially folded intermediates, not denatured chains.

Assembly of a tetrameric alpha-helical bundle: computer simulations on an intermediate-resolution protein model.

Discontinuous molecular dynamics (DMD) simulation on an intermediate-resolution protein model is used to study the folding of an isolated, small model peptide to an amphipathic alpha-helix and the assembly of four of these model peptides into a four-helix bundle. A total of 129 simulations were performed on the isolated peptide, and 50 simulations were performed on the four-peptide system. Simulations efficiently sample conformational space allowing complete folding trajectories from random initial configurations to be observed within 15 min for the one-peptide system and within 15 h for the four-peptide system on a 500-MHz workstation. The native structures of both the alpha-helix and the four-helix bundle are consistent with experimental characterization studies and with results from previous simulations on these model peptides. In both the one- and four-peptide systems, the native state is achieved during simulations within an optimal temperature range, a phenomenon also observed experimentally. The ease with which our simulations yield reasonable estimates of folded structures demonstrates the power of the intermediate-resolution model developed for this work and the DMD algorithm and suggests that simulations of very long times and of multiprotein systems may be possible with this model.

Group-velocity-matched three-wave mixing in birefringent crystals.

It is shown that the combination of pulse-front slant, kappa -vector tilt, and crystal birefringence often permits exact matching of both phase and group velocities for three-wave mixing in birefringent crystals. This exact match makes possible more-efficient mixing of short light pulses, and it permits efficient mixing of chirped or broadband light. I analyze this process and present examples.

Bypass of a meiotic checkpoint by overproduction of meiotic chromosomal proteins.

The Saccharomyces cerevisiae zip1 mutant, which exhibits defects in synaptonemal complex formation and meiotic recombination, triggers a checkpoint that causes cells to arrest at the pachytene stage of meiotic prophase. Overproduction of either the meiotic chromosomal protein Red1 or the meiotic kinase Mek1 bypasses this checkpoint, allowing zip1 cells to sporulate. Red1 or Mek1 overproduction also promotes sporulation of other mutants (zip2, dmc1, hop2) that undergo checkpoint-mediated arrest at pachytene. In addition, Red1 overproduction antagonizes interhomolog interactions in the zip1 mutant, substantially decreasing double-strand break formation, meiotic recombination, and homologous chromosome pairing. Mek1 overproduction, in contrast, suppresses checkpoint-induced arrest without significantly decreasing meiotic recombination. Cooverproduction of Red1 and Mek1 fails to bypass the checkpoint; moreover, overproduction of the meiotic chromosomal protein Hop1 blocks the Red1 and Mek1 overproduction phenotypes. These results suggest that meiotic chromosomal proteins function in the signaling of meiotic prophase defects and that the correct stoichiometry of Red1, Mek1, and Hop1 is needed to achieve checkpoint-mediated cell cycle arrest at pachytene.

Cloning and characterization of the Kluyveromyces lactis homologs of the Saccharomyces cerevisiae RED1 and HOP1 genes.

The synaptonemal complex (SC) is a meiosis-specific proteinaceous structure that holds homologous chromosomes close together along their length during the pachytene stage of meiotic prophase. The SC is observed in sexually reproducing fungi, plants and animals and is highly conserved at the cytological level. Despite this striking conservation of structure, however, the known protein components of the SC do not appear to be highly conserved across species. In Saccharomyces cerevisiae, the products of the RED1 and HOP1 genes are associated with the lateral elements of the SC. Using a functional complementation strategy, we have isolated homologs of these genes from the related yeast, Kluyveromyces lactis. The predicted K. lactis Red1 protein is 26% identical to the S. cerevisiae Red1 protein, and the K. lactis Hop1 protein is 40% identical to the S. cerevisiae Hop1 protein. The K. lactis RED1 gene fully complements the S. cerevisiae red1 mutant, both when overexpressed and when present in two copies in a diploid. However, the K. lactis HOP1 gene complements a hop1 mutant poorly when overproduced and not at all when present in two copies in a diploid. Unlike the S. cerevisiae RED1 gene, the K. lactis RED1 contains an intron; the transcript of the K. lactis gene is efficiently spliced during meiosis in S. cerevisiae.