S. pombe wtf drivers use dual transcriptional regulation and selective protein exclusion from spores to cause meiotic drive.

Meiotic drivers bias gametogenesis to ensure their transmission into more than half the offspring of a heterozygote. In Schizosaccharomyces pombe, wtf meiotic drivers destroy the meiotic products (spores) that do not inherit the driver from a heterozygote, thereby reducing fertility. wtf drivers encode both a Wtfpoison protein and a Wtfantidote protein using alternative transcriptional start sites. Here, we analyze how the expression and localization of the Wtf proteins are regulated to achieve drive. We show that transcriptional timing and selective protein exclusion from developing spores ensure that all spores are exposed to Wtf4poison, but only the spores that inherit wtf4 receive a dose of Wtf4antidote sufficient for survival. In addition, we show that the Mei4 transcription factor, a master regulator of meiosis, controls the expression of the wtf4poison transcript. This transcriptional regulation, which includes the use of a critical meiotic transcription factor, likely complicates the universal suppression of wtf genes without concomitantly disrupting spore viability. We propose that these features contribute to the evolutionary success of the wtf drivers.

Primary Repair, Reconstruction, and Suture Tape Augmentation All Provide Excellent Outcomes for Lateral Ligament Instability: A Systematic Review.

Purpose: To analyze the literature to compare outcomes and complications following primary lateral ankle ligament repair compared with lateral ankle ligament reconstruction and the suture tape augmentation in patients with lateral ankle instability. Methods: Following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) criteria, a systematic literature review using the PubMed/Ovid Medline database was performed (October 11, 1947, to October 1, 2019). Clinical trials that included all the following criteria were considered eligible; published in the English language; patients undergoing primary lateral ankle repair or reconstruction with/without autograft or allograft (anterior talofibular ligament, anterior talofibular ligament + calcaneofibular ligament) or suture tape augmentation; a follow-up at least 1 year; reported least 1 of the measured outcomes (The American Orthopaedic Foot Ankle Score, Karlsson Score, return to sport [RTS], complications, skin wound complications, reoperation). Surgical techniques were evaluated, and studies were subdivided by the following categories: primary repair (PR), reconstruction with graft (GR), and suture tape augmentation (STA). Complications, radiographic outcomes, functional outcome scores, and RTS were analyzed. Results: A total of 41 of 1,991 studies met the criteria for final analysis. This included 1,920 patients who underwent surgical intervention for chronic lateral instability with at least a 1-year follow-up. There were 350 patients who had GR, 1,486 who underwent the PR, and 84 who had STA. GR group appeared to have the lowest rate of complications: GR 3.1% (11 of 350), PR 4.2% (63 of 1486), and STA 10.7% (9 of 84). Postoperative American Orthopaedic Foot Ankle Score ranged from 89.0 to 95.1 for GR and 90.0 to 98.8 for PR. Postoperative Karlsson scores ranged from 80.9 to 94.4 for GR and from 89.2 to 94.1 for PR. Anterior drawer postoperative scores ranged from 1.4 to 30.3 mm for GR, 2.7 to 8.6 mm for PR, and 4.1 to 4.2 mm for STA. Postoperative talar tilt ranged from 2.4 to 7.3° for GR, 1.9 to 6.0° for PR, and 3.6 to 4.5° for STA. RTS ranged from 9.5 to 20.4 weeks for the PR group; one study reported a RTS of 10.6 weeks for STA. Conclusions: Excellent outcomes were noted across all intervention groups. Current literature may suggest there is no difference in functional outcomes between patients treated with PR versus GR. However, there may be a potential improvement in functional outcomes with PR versus STA. Level of Evidence: Level IV, systematic review of Level I to Level IV studies.

Comparing Sex-Specific Outcomes After Rotator Cuff Repair: A Meta-analysis.

Background: Rotator cuff repair (RCR) is a well-studied procedure. However, the impact of patient sex on outcomes after RCR has not been well studied. Purpose: To conduct a systematic review and meta-analysis of sex-based differences in outcomes after RCR and to record what proportion of studies examined this as a primary or secondary purpose. Study Design: Systematic review; Level of evidence, 4. Methods: A systematic review was performed using multiple databases according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Studies were included if they were written in English, performed on humans, consisted of patients who underwent RCR, evaluated at least 1 of the selected outcomes based on patient sex, and had statistical analysis available for their sex-based claim. Excluded were case reports, review studies, systematic reviews, cadaveric studies, and studies that did not report at least 1 sex-specific outcome or included certain other injuries associated with a rotator cuff injury. Results: Of 9998 studies screened and 1283 full-text studies reviewed, 11 (0.11%) studies with 2860 patients (1549 male and 1329 female) were included for quantitative analysis. None of these 11 studies examined the impact of patient sex on outcomes after RCR as a primary outcome. Postoperative Constant-Murley scores were analyzed for 7 studies. Male patients had a postoperative Constant-Murley score of 76.77 ± 15.94, while female patients had a postoperative Constant-Murley score of 69.88 ± 17.02. The random-effects model showed that male patients had significantly higher scores than female patients, with a mean difference of 7.33 (95% CI, 5.21-9.46; P < .0001). Analysis of retear rates in 5 studies indicated that there was no difference in the retear rate between sexes (odds ratio, 0.91 [95% CI, 0.49-1.67]). Conclusion: Female patients had lower postoperative Constant-Murley scores compared with male patients, but there was no difference in the retear rate. However, these results were based on an analysis of only 11 studies. The paucity of studies examining the impact of sex suggests that more research is needed on the impact of patient sex on outcomes after RCR.

Sex-Specific Outcomes After Anterior Cruciate Ligament Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: Despite the significant difference between men and women in incidence of anterior cruciate ligament (ACL) injuries, there is a paucity of consistent information on the influence of patient sex on outcomes after ACL reconstruction. A previous meta-analysis has demonstrated that female patients have worse outcomes with regard to laxity, revision rate, Lysholm score, and Tegner activity score and are less likely to return to sports (RTS). PURPOSE: To conduct a systematic review and meta-analysis to evaluate and compare sex-specific outcomes after ACL reconstruction. STUDY DESIGN: Systematic review; Level of evidence, 4. METHODS: A systematic review was performed using PubMed, PubMed Central, Embase, OVID, and Cochrane databases per PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The following search terms were used: "anterior cruciate ligament reconstruction" OR "ACL reconstruction" OR "anterior cruciate ligament" OR "ACL" AND "gender" OR "sex" OR "male" OR "female" AND "outcome" AND "2015-Present" to gather all relevant articles between 2015 and 2020. A risk-of-bias assessment and quality assessment was conducted on included studies. RESULTS: Of 9594 studies initially identified, 20 studies with 35,935 male and 21,455 female patients were included for analysis. The 7 studies reporting International Knee Documentation Committee (IKDC) scores showed that male patients had statistically significantly higher postoperative scores (mean difference, 3.02 [95% CI, 1.19-4.84]; P< .01; I 2 = 66%), and 7 studies that reported the rate of ACL revision showed there was no significant difference between male and female patients (odds ratio, 0.85 [95% CI, 0.45-1.60]; P = .61; I 2 = 94%). The 7 studies that reported rates of rerupture showed that males were significantly more likely than females to have a graft rerupture (odds ratio, 1.35 [95% CI, 1.22-1.50]; P < .01; I 2 = 0%). Male patients reported a higher RTS rate than did their female counterparts (59.82% compared with 42.89%); however, no formal statistical analysis could be done because of the variability in reporting techniques. CONCLUSION: Male and female patients with ACL injuries demonstrated similar outcomes regarding their rates of revision; however, male patients were found to have statistically significantly higher postoperative IKDC scores but at the same time higher rerupture rates. Our findings suggest that sex-based differences in outcomes after ACL reconstruction vary based on which metric is used. These results must be considered when counseling patients with ACL injuries.

The wtf4 meiotic driver utilizes controlled protein aggregation to generate selective cell death.

Meiotic drivers are parasitic loci that force their own transmission into greater than half of the offspring of a heterozygote. Many drivers have been identified, but their molecular mechanisms are largely unknown. The wtf4 gene is a meiotic driver in Schizosaccharomyces pombe that uses a poison-antidote mechanism to selectively kill meiotic products (spores) that do not inherit wtf4. Here, we show that the Wtf4 proteins can function outside of gametogenesis and in a distantly related species, Saccharomyces cerevisiae. The Wtf4poison protein forms dispersed, toxic aggregates. The Wtf4antidote can co-assemble with the Wtf4poison and promote its trafficking to vacuoles. We show that neutralization of the Wtf4poison requires both co-assembly with the Wtf4antidote and aggregate trafficking, as mutations that disrupt either of these processes result in cell death in the presence of the Wtf4 proteins. This work reveals that wtf parasites can exploit protein aggregate management pathways to selectively destroy spores.

Meiotic drivers are genes that break the normal rules of inheritance. Usually, a gene has a 50% chance of passing on to the next generation. Meiotic drivers force their way into the next generation by poisoning the gametes (the sex cells that combine to form a zygote) that do not carry them. Harnessing the power of genetic drivers could allow scientists to spread beneficial genes across populations. One group of meiotic drivers found in fission yeast is called the 'with transposon fission yeast', or 'wtf' gene family. The wtf drivers act during the production of spores, which are the fission yeast equivalent of sperm, and they encode both a poison that can destroy the spores and its antidote. The poison spreads through the sac holding the spores, and can affect all of them, while the antidote only protects the spores that make it. This means that the spores carrying the wtf genes survive, while the rest of the spores are killed. To understand whether it is possible to use the wtf meiotic drivers to spread other genes, perhaps outside of fission yeast, scientists must first establish exactly how the proteins coded for by genes behave. To do this, Nuckolls et al. examined a member of the wtf family called wtf4. Attaching a fluorescent label to the poison and antidote proteins produced by wtf4 made it possible to see what they do. This revealed that the poison clumps, forming toxic aggregates that damage yeast spores. The antidote works by mopping up these aggregates and moving them to the cell's main storage compartment, called the vacuole. Mutations that disrupted the ability of the antidote to interact with the poison or its ability to move the poison into storage stopped the antidote from working. Nuckolls et al. also showed that if genetic engineering was used to introduce wtf4 into a distantly related species of budding yeast the effects of this meiotic driver were the same. This suggests that the wtf genes may be good candidates for future genetic engineering experiments. Engineered systems known as 'gene drives' could spread beneficial genetic traits through populations. This could include disease-resistance genes in crops, or disease-preventing genes in mosquitoes. The wtf genes are small and work independently of other genes, making them promising candidates for this type of system. These experiments also suggest that the wtf genes could be useful for understanding why clumps of proteins are toxic to cells. Future work could explore why clumps of wtf poison kill spores, while clumps of poison plus antidote do not. This could aid research into human ailments caused by protein clumps, such as Huntington's or Alzheimer's disease.