A lack of genetic diversity and minimal adaptive evolutionary divergence in introduced Mysis shrimp after 50 years.

The successes of introduced populations in novel habitats often provide powerful examples of evolution and adaptation. In the 1950s, opossum shrimp (Mysis diluviana) individuals from Clearwater Lake in Minnesota, USA were transported and introduced to Twin Lakes in Colorado, USA by fisheries managers to supplement food sources for trout. Mysis were subsequently introduced from Twin Lakes into numerous lakes throughout Colorado. Because managers kept detailed records of the timing of the introductions, we had the opportunity to test for evolutionary divergence within a known time interval. Here, we used reduced representation genomic data to investigate patterns of genetic diversity, test for genetic divergence between populations, and for evidence of adaptive evolution within the introduced populations in Colorado. We found very low levels of genetic diversity across all populations, with evidence for some genetic divergence between the Minnesota source population and the introduced populations in Colorado. There was little differentiation among the Colorado populations, consistent with the known provenance of a single founding population, with the exception of the population from Gross Reservoir, Colorado. Demographic modeling suggests that at least one undocumented introduction from an unknown source population hybridized with the population in Gross Reservoir. Despite the overall low genetic diversity we observed, F ST outlier and environmental association analyses identified multiple loci exhibiting signatures of selection and adaptive variation related to elevation and lake depth. The success of introduced species is thought to be limited by genetic variation, but our results imply that populations with limited genetic variation can become established in a wide range of novel environments. From an applied perspective, the observed patterns of divergence between populations suggest that genetic analysis can be a useful forensic tool to determine likely sources of invasive species.

Targeted therapies in non-small cell lung cancer: present and future.

Lung cancer is the leading cause of malignancy-related death in the United States and the second most common cancer diagnosis worldwide. In the last two decades, lung cancer treatment has evolved to include advances in the development of mutation-based targeting, immunotherapy, radiation therapy, and minimally invasive surgical techniques. The discovery of lung cancer as a molecularly heterogeneous disease has driven investigation into the development of targeted therapies resulting in improved patient outcomes. Despite these advances, there remain opportunities, through further investigation of mechanisms of resistance, to develop novel therapeutics that better direct the personalization of lung cancer therapy. In this review, we highlight developments in the evolution of targeted therapies in non-small cell lung cancer, as well as future directions shaped by emerging patterns of resistance.

The role of elagolix in the suppression of ovulation in donor oocyte cycles.

Objective: To study the clinical use of elagolix in ovarian stimulation and its effect on premature ovulation in a cohort of women undergoing oocyte donation. Design: A prospective cohort study with the use of historical controls. Setting: A private reproductive endocrinology and infertility clinic. Patients: Seventy-five oocyte donors and 75 historical donors, aged 21-30 years, who had each passed Food and Drug Administration and American Society for Reproductive Medicine-approved oocyte donor screening. Interventions: Administration of elagolix 200 mg orally every night at bedtime with development of a follicular size of ≥14 mm for ovulation suppression compared with ganirelix 250 µg every night at bedtime. Main Outcome Measures: Premature ovulation rate, total oocytes, mature oocytes, maximum estradiol, luteinizing hormone, and progesterone levels. Results: Oocytes were available in all retrievals because there were no instances of premature ovulation in either the elagolix or ganirelix groups. There were no statistically significant differences between the groups in baseline demographics. Both groups had the same amounts of gonadotropins consumed and days of stimulation. The average number of total oocytes was similar between the control group and elagolix group (30.55 vs. 30.31). Furthermore, the average number of mature oocytes was similar between the control and study groups (25.42 vs. 24.73). An analysis of the 580 fresh oocytes in the elagolix group and the 737 fresh oocytes in the ganirelix group showed similar outcomes with fertilization rates of 79.7% and 84.6%, respectively. Blastocyst development rates were also similar: 62.9% in the elagolix group and 57.3% in the ganirelix group. Conclusions: Compared with a historical control group using ganirelix, patients receiving elagolix demonstrated a similar number of oocytes and mature oocytes with on average 4.2 fewer injections per cycle and average per-cycle patient savings of $289.10. Clinical Trial Registration Number: Western IRB Pr. No.: 20191163, April 11, 2019. First enrollment June 20, 2019.

Population genomics indicate three different modes of divergence and speciation with gene flow in the green-winged teal duck complex.

The processes leading to divergence and speciation can differ broadly among taxa with different life histories. We examine these processes in a small clade of ducks with historically uncertain relationships and species limits. The green-winged teal (Anas crecca) complex is a Holarctic species of dabbling duck currently categorized as three subspecies (Anas crecca crecca, A. c. nimia, and A. c. carolinensis) with a close relative, the yellow-billed teal (Anas flavirostris) from South America. A. c. crecca and A. c. carolinensis are seasonal migrants, while the other taxa are sedentary. We examined divergence and speciation patterns in this group, determining their phylogenetic relationships and the presence and levels of gene flow among lineages using both mitochondrial and genome-wide nuclear DNA obtained from 1,393 ultraconserved element (UCE) loci. Phylogenetic relationships using nuclear DNA among these taxa showed A. c. crecca, A. c. nimia, and A. c. carolinensis clustering together to form one polytomous clade, with A. flavirostris sister to this clade. This relationship can be summarized as (crecca, nimia, carolinensis)(flavirostris). However, whole mitogenomes revealed a different phylogeny: (crecca, nimia)(carolinensis, flavirostris). The best demographic model for key pairwise comparisons supported divergence with gene flow as the probable speciation mechanism in all three contrasts (crecca-nimia, crecca-carolinensis, and carolinensis-flavirostris). Given prior work, gene flow was expected among the Holarctic taxa, but gene flow between North American carolinensis and South American flavirostris (M âˆ¼0.1-0.4 individuals/generation), albeit low, was not expected. Three geographically oriented modes of divergence are likely involved in the diversification of this complex: heteropatric (crecca-nimia), parapatric (crecca-carolinensis), and (mostly) allopatric (carolinensis-flavirostris). Our study shows that ultraconserved elements are a powerful tool for simultaneously studying systematics and population genomics in systems with historically uncertain relationships and species limits.

Estimating Movement Rates Between Eurasian and North American Birds That Are Vectors of Avian Influenza.

Avian influenza (AI) is a zoonotic disease that will likely be involved in future pandemics. Because waterbird movements are difficult to quantify, determining the host-specific risk of Eurasian-origin AI movements into North America is challenging. We estimated relative rates of movements, based on long-term evolutionary averages of gene flow, between Eurasian and North American waterbird populations to obtain bidirectional baseline rates of the intercontinental movements of these AI hosts. We used population genomics and coalescent-based demographic models to obtain these gene-flow-based movement estimates. Inferred rates of movement between these continental populations varies greatly among species. Within dabbling ducks, gene flow, relative to effective population size, varies from ∼3 to 24 individuals/generation between Eurasian and American wigeons (Mareca penelope and Mareca americana) to ∼100-300 individuals/generation between continental populations of northern pintails (Anas acuta). These are evolutionary long-term averages and provide a solid foundation for understanding the relative risks of each of these host species in potential intercontinental AI movements. We scale these values to census size for evaluation in that context. In addition to being AI hosts, many of these bird species are also important in the subsistence diets of Alaskans, increasing the risk of direct bird-to-human exposure to Eurasian-origin AI virus. We contrast species-specific rates of intercontinental movements with the importance of each species in Alaskan diets to understand the relative risk of these taxa to humans. Assuming roughly equivalent AI infection rates among ducks, greater scaup (Aythya marila), mallard (Anas platyrhynchos), and northern pintail (Anas acuta) were the top three species presenting the highest risks for intercontinental AI movement both within the natural system and through exposure to subsistence hunters. Improved data on AI infection rates in this region could further refine these relative risk assessments. These directly comparable, species-based intercontinental movement rates and relative risk rankings should help in modeling, monitoring, and mitigating the impacts of intercontinental host and AI movements.

Estimación de las tasas de movimiento entre aves euroasiáticas y norteamericanas que son vectores de la influenza aviar. La influenza aviar es una enfermedad zoonótica que probablemente estará involucrada en futuras pandemias. Debido a que los movimientos de aves acuáticas son difíciles de cuantificar, La determinación del riesgo específico de hospedador de los movimientos de influenza aviar de origen euroasiático en América del Norte es un desafío. Se estimaron las tasas relativas de movimientos, sobre la base de promedios evolutivos a largo plazo del flujo de genes, entre las poblaciones de aves acuáticas euroasiáticas y norteamericanas para obtener tasas de referencia bidireccionales de los movimientos intercontinentales de estos huéspedes de influenza aviar. Se utilizó genómica de poblaciones y modelos demográficos basados en la teoría de la coalescencia para obtener estas estimaciones de movimiento basadas en el flujo de genes. Las tasas inferidas de movimiento entre estas poblaciones continentales varían mucho entre especies. Dentro de los patos chapuceros, el flujo de genes, en relación con el tamaño efectivo de la población, varía aproximadamente de 3 a 24 individuos/generación entre los silbones europeos y americanos (Mareca penelope y Mareca americana) hasta aproximadamente entre 100 a 300 individuos/generación entre poblaciones continentales de ánades rabudos (Anas acuta). Estos son promedios evolutivos a largo plazo y proporcionan una base sólida para comprender los riesgos relativos de cada una de estas especies hospedadoras en posibles movimientos intercontinentales de la influenza aviar. Se evaluaron estos valores al tamaño del censo para evaluarlos en ese contexto. Además de ser huéspedes de influenza aviar, muchas de estas especies de aves también son importantes en las dietas de subsistencia de los habitantes de Alaska, lo que aumenta el riesgo de exposición directa de las aves al ser humano por el virus de la influenza aviar de origen euroasiático. Se contrastaron las tasas específicas de especies de movimientos intercontinentales con la importancia de cada especie en las dietas de personas en Alaska para comprender el riesgo relativo de estos taxones para los humanos. Suponiendo tasas de infección por influenza aviar aproximadamente equivalentes entre patos, el porrón bastardo o pato boludo mayor (Aythya marila), el ánade real (Anas platyrhynchos) y el ánade rabudo eran las tres especies principales que presentaban los mayores riesgos para el movimiento de influenza aviar intercontinental tanto dentro del sistema natural como a través de la exposición a cazadores de subsistencia. La mejora de los datos sobre las tasas de infección por influenza aviar en esta región podría mejorar aún más estas evaluaciones de riesgo relativo. Estas tasas de movimiento intercontinental directamente comparables, basadas en especies, y clasificaciones de riesgo relativo deberían ayudar a modelar, monitorear y mitigar los impactos de los movimientos intercontinentales de huéspedes y de la influenza aviar.

Impaired Financial Decision-Making as an Early Indicator of Cognitive Decline: A Commentary.

Cognitive impairment and dementia are public health concerns with significant financial implications for both individual households and public insurance systems. Though research has refined diagnostic tools for cognitive impairment and dementia diseases, little attention has focused on how cognitive decline may impact financial security. Research indicates that financial decision-making may be one of the first cognitive abilities impacted by cognitive decline, putting individuals at risk of financial fraud and exploitation. However, financial decision-making is not directly assessed in cognitive screenings. Identification of prodromal decline in financial decision-making may help individuals to preserve their financial security and reduce the likelihood of relying on public benefits. This commentary outlines the need for social workers and researchers to better understand the relationship between cognitive health, financial decision-making, and financial security in later life to formulate culturally responsive strategies that can uphold and benefit financial statuses, especially for minoritized communities.

An empirical examination of sample size effects on population demographic estimates in birds using single nucleotide polymorphism (SNP) data.

Sample size is a critical aspect of study design in population genomics research, yet few empirical studies have examined the impacts of small sample sizes. We used datasets from eight diverging bird lineages to make pairwise comparisons at different levels of taxonomic divergence (populations, subspecies, and species). Our data are from loci linked to ultraconserved elements and our analyses used one single nucleotide polymorphism per locus. All individuals were genotyped at all loci, effectively doubling sample size for coalescent analyses. We estimated population demographic parameters (effective population size, migration rate, and time since divergence) in a coalescent framework using Diffusion Approximation for Demographic Inference, an allele frequency spectrum method. Using divergence-with-gene-flow models optimized with full datasets, we subsampled at sequentially smaller sample sizes from full datasets of 6-8 diploid individuals per population (with both alleles called) down to 1:1, and then we compared estimates and their changes in accuracy. Accuracy was strongly affected by sample size, with considerable differences among estimated parameters and among lineages. Effective population size parameters (ν) tended to be underestimated at low sample sizes (fewer than three diploid individuals per population, or 6:6 haplotypes in coalescent terms). Migration (m) was fairly consistently estimated until <2 individuals per population, and no consistent trend of over-or underestimation was found in either time since divergence (T) or theta (Θ = 4N refµ). Lineages that were taxonomically recognized above the population level (subspecies and species pairs; that is, deeper divergences) tended to have lower variation in scaled root mean square error of parameter estimation at smaller sample sizes than population-level divergences, and many parameters were estimated accurately down to three diploid individuals per population. Shallower divergence levels (i.e., populations) often required at least five individuals per population for reliable demographic inferences using this approach. Although divergence levels might be unknown at the outset of study design, our results provide a framework for planning appropriate sampling and for interpreting results if smaller sample sizes must be used.

Divergence, gene flow, and speciation in eight lineages of trans-Beringian birds.

Determining how genetic diversity is structured between populations that span the divergence continuum from populations to biological species is key to understanding the generation and maintenance of biodiversity. We investigated genetic divergence and gene flow in eight lineages of birds with a trans-Beringian distribution, where Asian and North American populations have likely been split and reunited through multiple Pleistocene glacial cycles. Our study transects the speciation process, including eight pairwise comparisons in three orders (ducks, shorebirds and passerines) at population, subspecies and species levels. Using ultraconserved elements (UCEs), we found that these lineages represent conditions from slightly differentiated populations to full biological species. Although allopatric speciation is considered the predominant mode of divergence in birds, all of our best divergence models included gene flow, supporting speciation with gene flow as the predominant mode in Beringia. In our eight lineages, three were best described by a split-migration model (divergence with gene flow), three best fit a secondary contact scenario (isolation followed by gene flow), and two showed support for both models. The lineages were not evenly distributed across a divergence space defined by gene flow (M) and differentiation (FST ), instead forming two discontinuous groups: one with relatively shallow divergence, no fixed single nucleotide polymorphisms (SNPs), and high rates of gene flow between populations; and the second with relatively deeply divergent lineages, multiple fixed SNPs, and low gene flow. Our results highlight the important role that gene flow plays in avian divergence in Beringia.

Clinical outcomes and financial impacts of malnutrition in sepsis.

BACKGROUND: In the United States in 2014 approximately 1.7 million adults were hospitalized with sepsis, resulting in about 270,000 deaths. Malnutrition in hospitalized patients contributes to increased morbidity, mortality, and costs, especially in the critically ill population. AIM: Our goal was to investigate the prevalence of malnutrition in sepsis and the impact it has on clinical and financial outcomes in our most critically ill patients. METHODS: We implemented nutritional screening by a registered dietitian of 1000 patients admitted with sepsis to specialized care units. We calculated the prevalence of malnutrition, and compared outcomes including mortality, length of stay, and financial costs. RESULTS: About 10% of patients with sepsis admitted to our specialized care units were diagnosed with malnutrition on admission after implementation of mandatory assessment. CONCLUSIONS: Although mortality did not reach statistical significance, these patients had more comorbidities, longer hospital stays, and higher total costs.

Inhibition of Hyaluronic Acid Synthesis Decreases Endometrial Cell Attachment, Migration, and Invasion.

To characterize the effects of 4-methylumbelliferone (4-MU) on expression of the hyaluronic acid (HA) system and on attachment, migration, and invasion of endometrial epithelial (EECs) and stroma cells (ESCs) to peritoneal mesothelial cells (PMCs), this in vitro study was performed in an Academic Center. De-identified endometrial tissue samples used were from reproductive-aged women. EECs and ESCs isolated from menstrual endometrial biopsies were treated with 4-MU or vehicle. Real-time polymerase chain reaction and western blot were used to assess expression of HA synthases (HAS), hyaluronidase, and standard CD44. Established in vitro assays were used to assess attachment, migration, and invasion with and without treatment with 4-MU. Chi square and Student's t-test were used to analyze the results as appropriate. The addition of 4-MU decreased mRNA and protein expression of HAS 2, HAS 3, and CD44 in EECs and ESCs compared to control. Treatment with 4-MU also decreased attachment, migration, and invasion of EECs and ESCs to PMCs compared to control. 4-MU decreases endometrial cell adhesion, migration, and invasion to PMCs. This effect appears to be mediated by a decrease in HAS 2, HAS 3, and CD44. 4-MU is a potential treatment for endometriosis. Future in vivo studies are needed to evaluate 4-MU as a therapeutic agent for endometriosis.

CD44 variant 6 is involved in the attachment and invasion of endometrial cells to peritoneum.

OBJECTIVE: To study the effects of CD44 standard (CD44s), CD44v3, and CD44v6 overexpression (OE) on immortalized human endometrial epithelial (iEECs) and stroma cells (human endometrial stromal cells [hESCs]) using in vitro assays and a nude mouse xenograft model. Menstrual endometrial cells from women with endometriosis have increased adhesion and also express higher levels of CD44 variant 6 (v6), but not v3, compared to menstrual endometrial cells from women without endometriosis. DESIGN: In vitro studies and in vivo xenograft model. SETTING: Academic center. PATIENTS(S): Deidentified immortalized endometrial epithelial tissue samples of a reproductive-age woman. INTERVENTION(S): Overexpression of CD44s, CD44v3, and CD44v6 was carried out using lipofectamine, and their expression was verified with mRNA and protein in iEEC and hESCs. The OE cells were used in in vitro studies and an in vivo xenograft model compared to plasmid control. MAIN OUTCOME MEASURE(S): The effect of CD44s, CD44v3, and CD44v6 OE on attachment and invasion assays and a xenograft model with immortalized human stromal and epithelial cells. RESULT(S): Expression of mRNA and protein confirmed appropriate OE of CD44s, CD44v3, and CD44v6 in the different cell types. CD44v6 OE increased attachment of hESCs compared with controls. CD44v6 OE did not change the attachment of iEECs. There was no difference in attachment in iEECs or hESCs with OE of CD44s or CD44v3. CONCLUSION(S): Overexpression of CD44v6 increases attachment of hESCs to peritoneal mesothelial cells in an in vitro assay and an in vivo xenograft model. Menstrual endometrial cell type and CD44 variants play a complex role in the development of the early endometriotic lesion.

Does assisted hatching affect live birth in fresh, first cycle in vitro fertilization in good and poor prognosis patients?

PURPOSE: To assess the effect of assisted hatching (AH) on live birth rate (LBR) in first cycle, fresh in vitro fertilization (IVF) in good and poor prognosis patients. METHODS: Retrospective cohort using cycles reported to the Society for Assisted Reproductive Technology Clinic Outcomes Reporting System. Live birth rate was compared in women who underwent first cycle, autologous, fresh IVF cycles with (n = 48,858) and without (n = 103,413) AH from 2007 to 2015. RESULTS: The propensity-weighted LBR was 39.2% with AH versus 43.9% without AH in all patients. The rate difference (RD) with AH was - 4.7% ([CI - 0.053, - 0.040], P < 0.001) with the calculated number needed to harm being 22. AH affected live birth in both good prognosis and poor prognosis patients. The propensity-weighted monozygotic twinning (MZT) rate was 2.3% in patients treated with AH as compared to 1.2% patients that did not receive AH. The RD with AH on MZT in fresh, first IVF cycles was 1.1% ([0.008, 0.014], P < 0.001). CONCLUSION: AH may affect LBR across all patients and in poor prognosis patients in fresh IVF cycles. Caution should be exercised when applying this technology. More prospective research is needed.

Speciation, gene flow, and seasonal migration in Catharus thrushes (Aves:Turdidae).

New World thrushes in the genus Catharus are small, insectivorous or omnivorous birds that have been used to explore several important questions in avian evolution, including the evolution of seasonal migration and plumage variation. Within Catharus, members of a clade of obligate long-distance migrants (C. fuscescens, C. minimus, and C. bicknelli) have also been used in the development of heteropatric speciation theory, a divergence process in which migratory lineages (which might occur in allopatry or sympatry during portions of their annual cycle) diverge despite low levels of gene flow. However, research on Catharus relationships has thus far been restricted to the use of small genetic datasets, which provide limited resolution of both phylogenetic and demographic histories. We used a large, multi-locus dataset from loci containing ultraconserved elements (UCEs) to study the demographic histories of the migratory C. fuscescens-minimus-bicknelli clade and to resolve the phylogeny of the migratory species of Catharus. Our dataset included more than 2000 loci and over 1700 variable genotyped sites, and analyses supported our prediction of divergence with gene flow in the fully migratory clade, with significant gene flow among all three species. Our phylogeny of the genus differs from past work in its placement of C. ustulatus, and further analyses suggest historic gene flow throughout the genus, producing genetically reticulate (or network) phylogenies. This raises questions about trait origins and suggests that seasonal migration and the resulting migratory condition of heteropatry is likely to promote hybridization not only during pairwise divergence and speciation, but also among non-sisters.

Prewash total motile count is a poor predictor of live birth in intrauterine insemination cycles.

OBJECTIVE: To determine whether there is a relationship between prewash total motile count and live births in couples undergoing IUI. DESIGN: Retrospective review in a single academic center. SETTING: Not applicable. PATIENT(S): Couples with infertility undergoing ovulation induction with IUI between 2010 and 2014. INTERVENTION(S): Not applicable. MAIN OUTCOME MEASURE(S): Live births. RESULT(S): Our cohort included 310 women who underwent 655 IUI cycles with a cumulative live birth rate (LBR) per couple of 20% and an LBR per cycle of 10%. A analysis yielded no correlation between prewash total motile count (TMC) and live births. No live births occurred with TMC <2 million sperms. Age had a significant negative relationship to LBR. A receiver operating characteristic analysis comparing age and live births indicated a significant decline in live births for women >37 years (90% sensitivity, 70% specificity). The LBR per couple was decreased to 7% in women >37 years compared with 25% in women <37 years. CONCLUSION(S): Prewash TMC is a poor predictor of live birth. There were no live births with prewash TMC <2 million sperms. The LBR for women >37 years with IUI was significantly lower than women <37 years.

The Hyaluronic Acid System is Intact in Menstrual Endometrial Cells in Women With and Without Endometriosis.

OBJECTIVE: To characterize the production and degradation of hyaluronic acid (HA) in menstrual endometrial epithelial cells (EECs) and endometrial stromal cells (ESCs) in women with and without endometriosis. To identify the presence of CD44, the primary receptor of HA, in menstrual EECs and ESCs in women with and without endometriosis. DESIGN: In vitro study. SETTING: Academic center. PATIENT(S): Deidentified patient samples from women with and without endometriosis. INTERVENTIONS: EECs and ESCs were isolated from menstrual endometrial biopsies performed on women with (N = 9) and without (N = 11) endometriosis confirmed by laparoscopy. MAIN OUTCOME MEASURE: Real-time polymerase chain reaction, Western blot, and immunohistochemistry were used to assess hyaluronic acid synthase (HAS) isoforms 1, 2, and 3; hyaluronidase (HYAL) isoforms 1 and 2; and standard CD44. Student t test was used to analyze the results. RESULTS: There was no significant difference in messenger RNA (mRNA) or protein expression of HAS2, HAS3, HYAL1, or HYAL2 in EECs or ESCs from women with or without endometriosis. HAS1 mRNA was variably detected, whereas HAS1 protein was similarly expressed in EECs and ESCs from women with and without endometriosis. Standard CD44 was expressed in both cell types, and expression did not differ in cells from women with or without endometriosis. CONCLUSIONS: The HA system is expressed in eutopic menstrual ESCs and EECs from women with and without endometriosis. There are no differences in expression in HA production or degradation enzymes in EECs or ESCs from women with and without endometriosis. Standard CD44 expression does not differ in eutopic menstrual endometrial cells from women with and without endometriosis.

Mediator Kinase Disruption in MED12-Mutant Uterine Fibroids From Hispanic Women of South Texas.

Context: Mutations in the gene encoding Mediator complex subunit MED12 are dominant drivers of uterine fibroids (UFs) in women of diverse racial and ethnic origins. Previously, we showed that UF-linked mutations in MED12 disrupt its ability to activate cyclin C-CDK8/19 in Mediator. However, validation of Mediator kinase disruption in the clinically relevant setting of MED12-mutant UFs is currently lacking. Objective: The objective of this study was twofold. First, to extend the ethnic distribution profile of MED12 mutations by establishing their frequency in UFs from Hispanic women of South Texas. Second, to examine the impact of MED12 mutations on Mediator kinase activity in patient-derived UFs. Methods: We screened 219 UFs from 76 women, including 170 tumors from 57 Hispanic patients, for MED12 exon 2 mutations, and further examined CDK8/19 activity in Mediator complexes immunoprecipitated from MED12 mutation-negative and MED12 mutation-positive UFs. Results: MED12 exon 2 mutations in UFs from Hispanic women are somatic in nature, predominantly monoallelic, and occur at high frequency (54.1%). We identified a minimal cyclin C-CDK8 activation domain on MED12 spanning amino acids 15 through 80 that includes all recorded UF-linked mutations in MED12, suggesting that disruption of Mediator kinase activity is a principal biochemical defect arising from these pathogenic alterations. Analysis of Mediator complexes recovered from patient UFs confirmed this, revealing that Mediator kinase activity is selectively impaired in MED12-mutant UFs. Conclusions: MED12 mutations are important drivers of UF formation in Hispanic women of South Texas. MED12 mutations disrupt Mediator kinase activity, implicating altered CDK8/19 function in UF pathogenesis.