Analysis of genetically determined gene expression suggests role of inflammatory processes in exfoliation syndrome.

BACKGROUND: Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. The largest global meta-analysis of XFS in 123,457 multi-ethnic individuals from 24 countries identified seven loci with the strongest association signal in chr15q22-25 region near LOXL1. Expression analysis have so far correlated coding and a few non-coding variants in the region with LOXL1 expression levels, but functional effects of these variants is unclear. We hypothesize that analysis of the contribution of the genetically determined component of gene expression to XFS risk can provide a powerful method to elucidate potential roles of additional genes and clarify biology that underlie XFS. RESULTS: Transcriptomic Wide Association Studies (TWAS) using PrediXcan models trained in 48 GTEx tissues leveraging on results from the multi-ethnic and European ancestry GWAS were performed. To eliminate the possibility of false-positive results due to Linkage Disequilibrium (LD) contamination, we i) performed PrediXcan analysis in reduced models removing variants in LD with LOXL1 missense variants associated with XFS, and variants in LOXL1 models in both multiethnic and European ancestry individuals, ii) conducted conditional analysis of the significant signals in European ancestry individuals, and iii) filtered signals based on correlated gene expression, LD and shared eQTLs, iv) conducted expression validation analysis in human iris tissues. We observed twenty-eight genes in chr15q22-25 region that showed statistically significant associations, which were whittled down to ten genes after statistical validations. In experimental analysis, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. TWAS genes for XFS were significantly enriched for genes associated with inflammatory conditions. We also observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. CONCLUSION: Our results implicate a role for connective tissues and inflammation pathways in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

Electronic health record phenotypes associated with genetically regulated expression of CFTR and application to cystic fibrosis.

PURPOSE: The increasing use of electronic health records (EHRs) and biobanks offers unique opportunities to study Mendelian diseases. We described a novel approach to summarize clinical manifestations from patient EHRs into phenotypic evidence for cystic fibrosis (CF) with potential to alert unrecognized patients of the disease. METHODS: We estimated genetically predicted expression (GReX) of cystic fibrosis transmembrane conductance regulator (CFTR) and tested for association with clinical diagnoses in the Vanderbilt University biobank (N = 9142 persons of European descent with 71 cases of CF). The top associated EHR phenotypes were assessed in combination as a phenotype risk score (PheRS) for discriminating CF case status in an additional 2.8 million patients from Vanderbilt University Medical Center (VUMC) and 125,305 adult patients including 25,314 CF cases from MarketScan, an independent external cohort. RESULTS: GReX of CFTR was associated with EHR phenotypes consistent with CF. PheRS constructed using the EHR phenotypes and weights discovered by the genetic associations improved discriminative power for CF over the initially proposed PheRS in both VUMC and MarketScan. CONCLUSION: Our study demonstrates the power of EHRs for clinical description of CF and the benefits of using a genetics-informed weighing scheme in construction of a phenotype risk score. This research may find broad applications for phenomic studies of Mendelian disease genes.

Life cycle assessment and economic analysis of anaerobic membrane bioreactor whole-plant configurations for resource recovery from domestic wastewater.

The use of the anaerobic membrane bioreactor (AnMBR) process for domestic wastewater treatment presents an opportunity to mitigate environmental, social, and economic impacts currently incurred from energy-intensive conventional aerobic activated sludge processes. Previous studies have performed detailed evaluations on improving AnMBR process subcomponents to maximize energy recovery and dissolved methane recovery. Few studies have broadly evaluated the role of chemical use, membrane fouling management, and dissolved methane removal technologies. A life cycle assessment was conducted to holistically compare multiple AnMBR-based domestic wastewater treatment trains to conventional activated sludge (CAS) treatment. These treatment trains included different scouring methods to mitigate membrane fouling (gas-sparging and granular activated carbon-fluidizing) with consideration of upstream treatment (primary sedimentation vs. screening only), downstream treatment (dissolved methane removal and nutrient removal) and sludge management (anaerobic digestion and lime stabilization). This study determined two process subcomponents (sulfide and phosphorus removal and sludge management) that drove chemical use and residuals generation, and in turn the environmental and cost impacts. Furthermore, integrating primary sedimentation and a vacuum degassing tank for dissolved methane removal maximized net energy recovery. Sustainability impacts were further mitigated by operating at a higher flux and temperature, as well as by substituting biological sulfide removal for chemical coagulation.

Long-Term Performance of a Pilot-Scale Gas-Sparged Anaerobic Membrane Bioreactor under Ambient Temperatures for Holistic Wastewater Treatment.

Concerns regarding ambient temperature operation, dissolved methane recovery, and nutrient removal have limited the implementation of anaerobic membrane bioreactors (AnMBRs) for domestic wastewater treatment. This study addresses these challenges using a pilot-scale gas-sparged AnMBR, with post-treatment recovery of dissolved methane and nutrients. Operating under ambient temperatures for 472 days, the AnMBR achieved an average effluent quality of 58 ± 27 mg/L COD and 25 ± 12 mg/L BOD5 at temperatures ranging from 12.7 to 31.5 °C. The average total methane yield was 0.14 ± 0.06 L-CH4/g-COD fed, with 42% of the total methane dissolved in the permeate. Dissolved methane removal using a hollow fiber membrane contactor achieved an average removal efficiency of 70 ± 5%, producing effluent dissolved methane concentrations of 3.8 ± 0.94 mg/L. The methane recovered from gaseous and dissolved fractions could generate an estimated 72.8% of the power required for energy neutrality. Nutrient recovery was accomplished using coagulation, flocculation, and sedimentation for removal of sulfide and phosphorus, followed by a clinoptilolite ion-exchange column for removal of ammonia, producing effluent concentrations of 0.7 ± 1.7 mg-S/L, 0.43 ± 0.29 mg-P/L and 0.05 ± 0.05 mg-N/L. The successful integration of AnMBRs in a treatment train that addresses the critical challenges of dissolved methane and nutrients demonstrates the viability of the technology in achieving holistic wastewater treatment.

Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture.

The direct estimation of heritability from genome-wide common variant data as implemented in the program Genome-wide Complex Trait Analysis (GCTA) has provided a means to quantify heritability attributable to all interrogated variants. We have quantified the variance in liability to disease explained by all SNPs for two phenotypically-related neurobehavioral disorders, obsessive-compulsive disorder (OCD) and Tourette Syndrome (TS), using GCTA. Our analysis yielded a heritability point estimate of 0.58 (se = 0.09, p = 5.64e-12) for TS, and 0.37 (se = 0.07, p = 1.5e-07) for OCD. In addition, we conducted multiple genomic partitioning analyses to identify genomic elements that concentrate this heritability. We examined genomic architectures of TS and OCD by chromosome, MAF bin, and functional annotations. In addition, we assessed heritability for early onset and adult onset OCD. Among other notable results, we found that SNPs with a minor allele frequency of less than 5% accounted for 21% of the TS heritability and 0% of the OCD heritability. Additionally, we identified a significant contribution to TS and OCD heritability by variants significantly associated with gene expression in two regions of the brain (parietal cortex and cerebellum) for which we had available expression quantitative trait loci (eQTLs). Finally we analyzed the genetic correlation between TS and OCD, revealing a genetic correlation of 0.41 (se = 0.15, p = 0.002). These results are very close to previous heritability estimates for TS and OCD based on twin and family studies, suggesting that very little, if any, heritability is truly missing (i.e., unassayed) from TS and OCD GWAS studies of common variation. The results also indicate that there is some genetic overlap between these two phenotypically-related neuropsychiatric disorders, but suggest that the two disorders have distinct genetic architectures.

Genetic association signal near NTN4 in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.

Discovery and functional assessment of gene variants in the vascular endothelial growth factor pathway.

Angiogenesis is a host-mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis-related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis-eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis-eQTLs provided mechanistic evidence for two genome-wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role.

Pyrosequencing analysis yields comprehensive assessment of microbial communities in pilot-scale two-stage membrane biofilm reactors.

We studied the microbial community structure of pilot two-stage membrane biofilm reactors (MBfRs) designed to reduce nitrate (NO3(-)) and perchlorate (ClO4(-)) in contaminated groundwater. The groundwater also contained oxygen (O2) and sulfate (SO4(2-)), which became important electron sinks that affected the NO3(-) and ClO4(-) removal rates. Using pyrosequencing, we elucidated how important phylotypes of each "primary" microbial group, i.e., denitrifying bacteria (DB), perchlorate-reducing bacteria (PRB), and sulfate-reducing bacteria (SRB), responded to changes in electron-acceptor loading. UniFrac, principal coordinate analysis (PCoA), and diversity analyses documented that the microbial community of biofilms sampled when the MBfRs had a high acceptor loading were phylogenetically distant from and less diverse than the microbial community of biofilm samples with lower acceptor loadings. Diminished acceptor loading led to SO4(2-) reduction in the lag MBfR, which allowed Desulfovibrionales (an SRB) and Thiothrichales (sulfur-oxidizers) to thrive through S cycling. As a result of this cooperative relationship, they competed effectively with DB/PRB phylotypes such as Xanthomonadales and Rhodobacterales. Thus, pyrosequencing illustrated that while DB, PRB, and SRB responded predictably to changes in acceptor loading, a decrease in total acceptor loading led to important shifts within the "primary" groups, the onset of other members (e.g., Thiothrichales), and overall greater diversity.

Transcriptome-Wide Association Studies (TWAS): Methodologies, Applications, and Challenges.

Transcriptome-wide association study (TWAS) methodologies aim to identify genetic effects on phenotypes through the mediation of gene transcription. In TWAS, in silico models of gene expression are trained as functions of genetic variants and then applied to genome-wide association study (GWAS) data. This post-GWAS analysis identifies gene-trait associations with high interpretability, enabling follow-up functional genomics studies and the development of genetics-anchored resources. We provide an overview of commonly used TWAS approaches, their advantages and limitations, and some widely used applications. © 2024 Wiley Periodicals LLC.

Impact of Tumor-intrinsic Molecular Features on Survival and Acquired Tyrosine Kinase Inhibitor Resistance in ALK-positive NSCLC.

While tyrosine kinase inhibitors (TKI) have shown remarkable efficacy in anaplastic lymphoma kinase (ALK) fusion-positive advanced non-small cell lung cancer (NSCLC), clinical outcomes vary and acquired resistance remains a significant challenge. We conducted a retrospective study of patients with ALK-positive NSCLC who had clinico-genomic data independently collected from two academic institutions (n = 309). This was paired with a large-scale genomic cohort of patients with ALK-positive NSCLC who underwent liquid biopsies (n = 1,118). Somatic co-mutations in TP53 and loss-of-function alterations in CDKN2A/B were most commonly identified (24.1% and 22.5%, respectively in the clinical cohort), each of which was independently associated with inferior overall survival (HR: 2.58; 95% confidence interval, CI: 1.62-4.09 and HR: 1.93; 95% CI: 1.17-3.17, respectively). Tumors harboring EML4-ALK variant 3 (v3) were not associated with specific co-alterations but were more likely to develop ALK resistance mutations, particularly G1202R and I1171N (OR: 4.11; P < 0.001 and OR: 2.94; P = 0.026, respectively), and had inferior progression-free survival on first-line TKI (HR: 1.52; 95% CI: 1.03-2.25). Non-v3 tumors were associated with L1196M resistance mutation (OR: 4.63; P < 0.001). EML4-ALK v3 and somatic co-alterations in TP53 and CDKN2A/B are associated with inferior clinical outcomes. v3 status is also associated with specific patterns of clinically important ALK resistance mutations. These tumor-intrinsic features may inform rational selection and optimization of first-line and consolidative therapy. SIGNIFICANCE: In a large-scale, contemporary cohort of patients with advanced ALK-positive NSCLC, we evaluated molecular characteristics and their impact on acquired resistance mutations and clinical outcomes. Our findings that certain ALK variants and co-mutations are associated with differential survival and specific TKI-relevant resistance patterns highlight potential molecular underpinnings of the heterogenous response to ALK TKIs and nominate biomarkers that may inform patient selection for first-line and consolidative therapies.

Rate of molecular evolution of the seminal protein gene SEMG2 correlates with levels of female promiscuity.

Postcopulatory sperm competition is a key aspect of sexual selection and is believed to drive the rapid evolution of both reproductive physiology and reproduction-related genes. It is well-established that mating behavior determines the intensity of sperm competition, with polyandry (i.e., female promiscuity) leading to fiercer sperm competition than monandry. Studies in mammals, particularly primates, showed that, owing to greater sperm competition, polyandrous taxa generally have physiological traits that make them better adapted for fertilization than monandrous species, including bigger testes, larger seminal vesicles, higher sperm counts, richer mitochondrial loading in sperm and more prominent semen coagulation. Here, we show that the degree of polyandry can also impact the dynamics of molecular evolution. Specifically, we show that the evolution of SEMG2, the gene encoding semenogelin II, a main structural component of semen coagulum, is accelerated in polyandrous primates relative to monandrous primates. Our study showcases the intimate relationship between sexual selection and the molecular evolution of reproductive genes.

Evaluation of an Initial Specimen Diversion Device (ISDD) on Rates of Blood Culture Contamination in the Emergency Department.

INTRODUCTION: Blood cultures are the gold standard for identifying bloodstream infections. The Clinical and Laboratory Standards Institute recommends a blood culture contamination rate of less than 3%. Contamination can lead to misdiagnosis, increased length of stay and hospital costs, unnecessary testing, and antibiotic use. These reasons led to the development of initial specimen diversion devices (ISDD). The purpose of this study was to evaluate the impact of an initial specimen diversion device on rates of blood culture contamination in the emergency department. METHODS: This was a retrospective, multi-site study including patients who had blood cultures drawn in an emergency department. February 2018 to April 2018, when an ISDD was not utilized, was compared with June 2019 to August 2019, when an ISDD was being used. The primary outcome was total blood culture contamination. Secondary outcomes were total hospital cost, hospital and intensive care unit length of stay, vancomycin duration of use, vancomycin serum concentrations obtained, and repeat blood cultures obtained. RESULTS: A statistically significant difference was found in blood culture contamination rates in the pre-ISDD group vs. the ISDD group (7.47% vs. 2.59%, p < 0.001). None of the secondary endpoints showed a statistically significant difference. CONCLUSIONS: Implementation of an ISDD reduced blood culture contamination. When implementing the ISDD to a healthcare system, compliance is important and will affect contamination rates dramatically.

In situ bioremediation of perchlorate in vadose zone soil using gaseous electron donors: microcosm treatability study.

A series of microcosm experiments were performed to determine the effectiveness of various gaseous electron donors (including hydrogen, 1-hexene, ethyl acetate, and liquefied petroleum gas [LPG]) for supporting biological perchlorate reduction under different electron donor concentrations and soil moistures. Under high soil moisture (16% w/w) conditions, complete or partial perchlorate degradation was achieved with all of the tested electron donors, except for ethyl acetate. Hydrogen was the most promising of the tested electron donors, achieving complete perchlorate degradation with first-order rate constants ranging from 0.13 to 0.20 day(-1) and reducing concentrations to non-detectable levels within 35 to 42 days. The LPG and 1-hexene each promoted partial perchlorate reduction, with average first-order rate constants of 0.05 and 0.11 day(-1), respectively. Although significant perchlorate reduction was observed with as little as 13% moisture, the moisture content for complete perchlorate degradation in this particular soil was determined to be 17%.

The regulatory genome constrains protein sequence evolution: implications for the search for disease-associated genes.

The development of explanatory models of protein sequence evolution has broad implications for our understanding of cellular biology, population history, and disease etiology. Here we analyze the GTEx transcriptome resource to quantify the effect of the transcriptome on protein sequence evolution in a multi-tissue framework. We find substantial variation among the central nervous system tissues in the effect of expression variance on evolutionary rate, with highly variable genes in the cortex showing significantly greater purifying selection than highly variable genes in subcortical regions (Mann-Whitney U p = 1.4 × 10-4). The remaining tissues cluster in observed expression correlation with evolutionary rate, enabling evolutionary analysis of genes in diverse physiological systems, including digestive, reproductive, and immune systems. Importantly, the tissue in which a gene attains its maximum expression variance significantly varies (p = 5.55 × 10-284) with evolutionary rate, suggesting a tissue-anchored model of protein sequence evolution. Using a large-scale reference resource, we show that the tissue-anchored model provides a transcriptome-based approach to predicting the primary affected tissue of developmental disorders. Using gradient boosted regression trees to model evolutionary rate under a range of model parameters, selected features explain up to 62% of the variation in evolutionary rate and provide additional support for the tissue model. Finally, we investigate several methodological implications, including the importance of evolutionary-rate-aware gene expression imputation models using genetic data for improved search for disease-associated genes in transcriptome-wide association studies. Collectively, this study presents a comprehensive transcriptome-based analysis of a range of factors that may constrain molecular evolution and proposes a novel framework for the study of gene function and disease mechanism.

Long-term microbial community dynamics in a pilot-scale gas sparged anaerobic membrane bioreactor treating municipal wastewater under seasonal variations.

This study evaluates the microbial community development in the suspended sludge within a pilot-scale gas sparged Anaerobic membrane bioreactor (AnMBR) under ambient conditions, as well as understand the influence of microbial signatures in the influent municipal wastewater on the bioreactor using amplicon sequence analysis. The predominant bacterial phyla comprised of Bacteroidetes, Proteobacteria, Firmicutes, and Chloroflexi demonstrated resiliency with ambient temperature operation over a period of 472 days. Acetoclastic Methanosaeta were predominant during most of the AnMBR operation. Beta diversity analysis indicated that the microbial communities present in the influent wastewater did not affect the AnMBR core microbiome. Syntrophic microbial interactions were evidenced by the presence of the members from Synergistales, Anaerolineales, Clostridiales, and Syntrophobacterales. The proliferation of sulfate reducing bacteria (SRB) along with sulfate reduction underscored the competition of SRB in the AnMBR. Operational and environmental variables did not greatly alter the core bacterial population based on canonical correspondence analysis.

Holmium Laser Enucleation of the Prostate Is Safe and Feasible as a Same Day Surgery.

OBJECTIVE: To assess the safety, feasibility and treatment outcomes of holmium laser enucleation of the prostate (HoLEP) as a same day surgery (SDS). METHODS: HoLEPs performed from November 2013 to December 2018 at our institution were reviewed retrospectively. Inclusion criteria for same day surgery (SDS) included living in the local metropolitan area with access to local hospital and Eastern Cooperative Oncology Group (ECOG) 0-2, regardless of prostate size and anticoagulation status. Those patients who were discharged directly from the postoperative care unit were identified as SDS cases. Patients admitted overnight after HoLEP during the same period were used as a matched cohort. Patient demographics, disease characteristics and treatment outcomes were compared. RESULTS: A total of 377 patients were identified, including 199 SDS and 178 non-SDS patients. No statistical difference was present between the 2 groups regarding the post-op complication and readmission rates. The non-SDS group had a significantly higher percentage of patients with history of urinary retention, lower pre-op Qmax, and larger prostate volume. The SDS group had shorter operative time, length of stay (LOS), and catherization time (all P <.05). At 1-year follow-up, no statistically different change in Qmax, PVR, or IPSS score was noted between the 2 groups. CONCLUSION: Same day outpatient surgery for HoLEP is safe in patients who live in close proximity and have ECOG status 0-2. Our readmission rate and complication rate are comparable to those reported in the literature with markedly decreased LOS. Long-term functional outcome is not compromised by SDS.

The impact of sex on gene expression across human tissues.

Many complex human phenotypes exhibit sex-differentiated characteristics. However, the molecular mechanisms underlying these differences remain largely unknown. We generated a catalog of sex differences in gene expression and in the genetic regulation of gene expression across 44 human tissue sources surveyed by the Genotype-Tissue Expression project (GTEx, v8 release). We demonstrate that sex influences gene expression levels and cellular composition of tissue samples across the human body. A total of 37% of all genes exhibit sex-biased expression in at least one tissue. We identify cis expression quantitative trait loci (eQTLs) with sex-differentiated effects and characterize their cellular origin. By integrating sex-biased eQTLs with genome-wide association study data, we identify 58 gene-trait associations that are driven by genetic regulation of gene expression in a single sex. These findings provide an extensive characterization of sex differences in the human transcriptome and its genetic regulation.

Slow-release permanganate versus unactivated persulfate for long-term in situ chemical oxidation of 1,4-dioxane and chlorinated solvents.

The objective of this research was to evaluate slow-release permanganate and unactivated persulfate for in situ treatment of dioxane and associated chlorinated solvents. Laboratory batch studies with unactivated persulfate in deionized water or in soil and groundwater demonstrated dioxane removal with pseudo second-order rate constants ranging from 10-5 to 10-3 M-1 s-1. Flow-through column studies demonstrated over 99% dioxane removal with slow-release unactivated persulfate but not with slow-release permanganate. The slow-release permanganate cylinders became coated with a rind that limited oxidant mass transfer and dioxane oxidation. A field study was conducted with slow-release persulfate cylinders transverse to groundwater flow. Over 99% removal of dioxane and chlorinated solvents was observed 2.5 m downgradient of the cylinders. Density-driven flow associated with the released persulfate was observed and was attributed to a low horizontal hydraulic gradient. Thus, most of the contaminant and persulfate flux was thought to be isolated to a deep aquifer zone that was bound by an underlying silt aquitard. Contaminant reductions were also observed in shallow groundwater samples, albeit at a lesser extent. The longevity of the persulfate oxidant cylinders was estimated to be 6-12 months. Results of this study demonstrate that dioxane and co-mingled chlorinated solvents can be effectively treated using slow-release persulfate cylinders. Careful consideration to cylinder placement during the design phase is essential to prevent the contaminant plume from bypassing and not coming into contact with the released oxidant.

A comparative pilot-scale evaluation of gas-sparged and granular activated carbon-fluidized anaerobic membrane bioreactors for domestic wastewater treatment.

Two significantly different pilot-scale AnMBRs were used to treat screened domestic wastewater for over one year. Both systems similarly reduced BOD5 and COD by 86-90% within a 13-32 °C temperature range and at comparable COD loading rates of 1.3-1.4 kg-COD m-3 d-1 and membrane fluxes of 7.6-7.9 L m-2 h-1 (LMH). However, the GAC-fluidized AnMBR achieved these results at a 65% shorter hydraulic retention time than the gas-sparged AnMBR. The gas-sparged AnMBR was able to operate at a similar operating permeability with greater reactor concentrations of suspended solids and colloidal organics than the GAC-fluidized AnMBR. Also, the membranes were damaged more in the GAC-fluidized system. To better capture the relative advantages of each system a hybrid AnMBR comprised of a GAC-fluidized bioreactor connected to a separate gas-sparged ultrafiltration membrane system is proposed. This will likely be more effective, efficient, robust, resilient, and cost-effective.

Inferred divergent gene regulation in archaic hominins reveals potential phenotypic differences.

Sequencing DNA derived from archaic bones has enabled genetic comparison of Neanderthals and anatomically modern humans (AMHs), and revealed that they interbred. However, interpreting what genetic differences imply about their phenotypic differences remains challenging. Here, we introduce an approach for identifying divergent gene regulation between archaic hominins, such as Neanderthals, and AMH sequences, and find 766 genes that are likely to have been divergently regulated (DR) by Neanderthal haplotypes that do not remain in AMHs. DR genes include many involved in phenotypes known to differ between Neanderthals and AMHs, such as the structure of the rib cage and supraorbital ridge development. They are also enriched for genes associated with spontaneous abortion, polycystic ovary syndrome, myocardial infarction and melanoma. Phenotypes associated with modern human variation in these genes' regulation in ~23,000 biobank patients further support their involvement in immune and cardiovascular phenotypes. Comparing DR genes between two Neanderthals and a Denisovan revealed divergence in the immune system and in genes associated with skeletal and dental morphology that are consistent with the archaeological record. These results establish differences in gene regulatory architecture between AMHs and archaic hominins, and provide an avenue for exploring phenotypic differences between archaic groups from genomic information alone.