•Direct contact membrane distillation was used to desalinate hypersaline brines.•Crystallization of supersaturated NaCl on the membrane was reversible.•Crystallization of supersaturated Great Salt ...Lake brine was irreversible.•Membrane pores were impacted by mineral crystallization during DCMD desalination.
Membrane distillation (MD) is a thermally-driven separation process that utilizes a difference in vapor pressure across a porous, hydrophobic membrane as the driving force. MD may be applied to aqueous systems at concentrations up to and exceeding saturation of both sparingly soluble salts and soluble salts such as sodium chloride (NaCl), leading to potential application in high-recovery desalination processes that approach Zero Liquid Discharge (ZLD) operation, or as a concentration strategy for mineral recovery. Scaling and fouling is a significant risk for such processes, and knowledge of the effects of these phenomena on performance is essential to the evaluation of MD as a viable technology for these applications. The present study investigated the scaling and fouling behavior of a hypersaline brine collected from the North Arm of the Great Salt Lake (GSL), which was nearly saturated with respect to NaCl, and also contained high concentrations of dissolved minerals and organic carbon. Effects on water flux, thermal efficiency, and salt rejection were measured, and membranes used were analyzed before and after testing to evaluate potential causes of these effects. Scaling by NaCl crystallization on the membrane surface limited water recovery to approximately 10%, and also caused damage to the internal pore structure of the membrane when the temperature difference (ΔT) between the feed and distillate was higher than 20°C. Analysis of the solution chemistry of the GSL water was effective in predicting the scaling tendency of NaCl, but inadequate in predicting the scaling tendency of other salts. Amorphous scaling structures on the membrane surfaces containing magnesium and oxygen were implied as the dominant factors contributing to performance decline at concentrations below NaCl saturation, and the result of fouling due to interactions between organic matter and magnesium. Operation at a maximum water recovery of 8% combined with intermittent reversal of the temperature gradient were effective strategies to prevent both scaling and fouling and maintain long-term performance.
Membrane scaling by silica is a major challenge in desalination, particularly for inland desalination of brackish groundwater or geothermal water, which often contain high concentrations of silica ...and dissolved solids. Adjustment of feed pH may reduce silica scaling risk, which is important for inland facilities that operate at high water recoveries to reduce brine disposal costs. However, water recovery of reverse osmosis is also limited due to increased osmotic pressure with feed water concentration. Membrane distillation (MD) is a thermally driven membrane desalination technique that is not limited by increased osmotic pressure of the feed. In this investigation, pH adjustment was tested as a strategy to reduce silica scaling risk in the MD process. With feed water pH less than 5 or higher than 10, scaling impacts were negligible at silica concentrations up to 600 mg/L. Scaling rates were highest at neutral pH between 6 and 8. Cleaning strategies were also explored to remove silica scale from membranes. Cleaning using NaOH solutions at pH higher than 11 to induce dissolution of silica scale was effective at temporarily restoring performance; however, some silica remained on membrane surfaces and scaling upon re-exposure to supersaturated silica concentrations occurred faster than with new membranes.
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•Silica scaling in membrane distillation can be reduced with feed pH adjustment.•At similar pH and concentration, scaling rates correlate to polymerization rates.•Acidification is less costly than alkalization for comparable scale reduction.•Silica scale may be partially removed by rinsing with NaOH solution.•Silica scale has negligible impact on MD performance with temperatures reversed.
Many modern human genomes retain DNA inherited from interbreeding with archaic hominins, such as Neandertals, yet the influence of this admixture on human traits is largely unknown. We analyzed the ...contribution of common Neandertal variants to over 1000 electronic health record (EHR)–derived phenotypes in ~28,000 adults of European ancestry. We discovered and replicated associations of Neandertal alleles with neurological, psychiatric, immunological, and dermatological phenotypes. Neandertal alleles together explained a significant fraction of the variation in risk for depression and skin lesions resulting from sun exposure (actinic keratosis), and individual Neandertal alleles were significantly associated with specific human phenotypes, including hypercoagulation and tobacco use. Our results establish that archaic admixture influences disease risk in modern humans, provide hypotheses about the effects of hundreds of Neandertal haplotypes, and demonstrate the utility of EHR data in evolutionary analyses.
The importance of epistasis—or statistical interactions between genetic variants—to the development of complex disease in humans has been controversial. Genome-wide association studies of statistical ...interactions influencing human traits have recently become computationally feasible and have identified many putative interactions. However, statistical models used to detect interactions can be confounded, which makes it difficult to be certain that observed statistical interactions are evidence for true molecular epistasis. In this study, we investigate whether there is evidence for epistatic interactions between genetic variants within the cis-regulatory region that influence gene expression after accounting for technical, statistical, and biological confounding factors. We identified 1,119 (FDR = 5%) interactions that appear to regulate gene expression in human lymphoblastoid cell lines, a tightly controlled, largely genetically determined phenotype. Many of these interactions replicated in an independent dataset (90 of 803 tested, Bonferroni threshold). We then performed an exhaustive analysis of both known and novel confounders, including ceiling/floor effects, missing genotype combinations, haplotype effects, single variants tagged through linkage disequilibrium, and population stratification. Every interaction could be explained by at least one of these confounders, and replication in independent datasets did not protect against some confounders. Assuming that the confounding factors provide a more parsimonious explanation for each interaction, we find it unlikely that cis-regulatory interactions contribute strongly to human gene expression, which calls into question the relevance of cis-regulatory interactions for other human phenotypes. We additionally propose several best practices for epistasis testing to protect future studies from confounding.
The spatial distribution of genetic variation within proteins is shaped by evolutionary constraint and provides insight into the functional importance of protein regions and the potential ...pathogenicity of protein alterations. Here, we comprehensively evaluate the 3D spatial patterns of human germline and somatic variation in 6,604 experimentally derived protein structures and 33,144 computationally derived homology models covering 77% of all human proteins. Using a systematic approach, we quantify differences in the spatial distributions of neutral germline variants, disease-causing germline variants, and recurrent somatic variants. Neutral missense variants exhibit a general trend toward spatial dispersion, which is driven by constraint on core residues. In contrast, germline disease-causing variants are generally clustered in protein structures and form clusters more frequently than recurrent somatic variants identified from tumor sequencing. In total, we identify 215 proteins with significant spatial constraints on the distribution of disease-causing missense variants in experimentally derived protein structures, only 65 (30%) of which have been previously reported. This analysis identifies many clusters not detectable from sequence information alone; only 12% of proteins with significant clustering in 3D were identified from similar analyses of linear protein sequence. Furthermore, spatial analyses of mutations in homology-based structural models are highly correlated with those from experimentally derived structures, supporting the use of computationally derived models. Our approach highlights significant differences in the spatial constraints on different classes of mutations in protein structure and identifies regions of potential function within individual proteins.
Next-generation sequencing of individuals with genetic diseases often detects candidate rare variants in numerous genes, but determining which are causal remains challenging. We hypothesized that the ...spatial distribution of missense variants in protein structures contains information about function and pathogenicity that can help prioritize variants of unknown significance (VUS) and elucidate the structural mechanisms leading to disease.
To illustrate this approach in a clinical application, we analyzed 13 candidate missense variants in regulator of telomere elongation helicase 1 (RTEL1) identified in patients with Familial Interstitial Pneumonia (FIP). We curated pathogenic and neutral RTEL1 variants from the literature and public databases. We then used homology modeling to construct a 3D structural model of RTEL1 and mapped known variants into this structure. We next developed a pathogenicity prediction algorithm based on proximity to known disease causing and neutral variants and evaluated its performance with leave-one-out cross-validation. We further validated our predictions with segregation analyses, telomere lengths, and mutagenesis data from the homologous XPD protein. Our algorithm for classifying RTEL1 VUS based on spatial proximity to pathogenic and neutral variation accurately distinguished 7 known pathogenic from 29 neutral variants (ROC AUC = 0.85) in the N-terminal domains of RTEL1. Pathogenic proximity scores were also significantly correlated with effects on ATPase activity (Pearson r = -0.65, p = 0.0004) in XPD, a related helicase. Applying the algorithm to 13 VUS identified from sequencing of RTEL1 from patients predicted five out of six disease-segregating VUS to be pathogenic. We provide structural hypotheses regarding how these mutations may disrupt RTEL1 ATPase and helicase function.
Spatial analysis of missense variation accurately classified candidate VUS in RTEL1 and suggests how such variants cause disease. Incorporating spatial proximity analyses into other pathogenicity prediction tools may improve accuracy for other genes and genetic diseases.
The relationship between eczema, wheeze or asthma, and rhinitis is complex, and epidemiology and mechanisms of their comorbidities is unclear.
To investigate within-individual patterns of morbidity ...of eczema, wheeze, and rhinitis from birth to adolescence/early adulthood.
We investigated onset, progression, and resolution of eczema, wheeze, and rhinitis using descriptive statistics, sequence mining, and latent Markov modeling in four population-based birth cohorts. We used logistic regression to ascertain if early-life eczema or wheeze, or genetic factors (
mutations and 17q21 variants), increase the risk of multimorbidity.
Single conditions, although the most prevalent, were observed significantly less frequently than by chance. There was considerable variation in the timing of onset/remission/persistence/intermittence. Multimorbidity of eczema+wheeze+rhinitis was rare but significantly overrepresented (three to six times more often than by chance). Although infantile eczema was associated with subsequent multimorbidity, most children with eczema (75.4%) did not progress to any multimorbidity pattern.
mutations and rs7216389 were not associated with persistence of eczema/wheeze as single conditions, but both increased the risk of multimorbidity (
by 2- to 3-fold, rs7216389 risk variant by 1.4- to 1.7-fold). Latent Markov modeling revealed five latent states (no disease/low risk, mainly eczema, mainly wheeze, mainly rhinitis, multimorbidity). The most likely transition to multimorbidity was from eczema state (0.21). However, although this was one of the highest transition probabilities, only one-fifth of those with eczema transitioned to multimorbidity.
Atopic diseases fit a multimorbidity framework, with no evidence for sequential atopic march progression. The highest transition to multimorbidity was from eczema, but most children with eczema (more than three-quarters) had no comorbidities.
Desalination of inland water resources such as brackish groundwater or geothermal water must achieve high water recovery to minimize reject brine volume and costs associated with its disposal. ...Pressure-driven membrane processes such as reverse osmosis (RO) and nanofiltration (NF) are presently the most commonly used technologies for desalination of brackish water; however, water recovery is often limited due to high scaling potential by silica, calcium, magnesium, and other minerals. Membrane distillation (MD), a thermally driven membrane process, is commonly tolerant to high salinity and may be less prone to irreversible fouling by mineral scaling. This investigation compared performance and fouling behavior of MD and NF during concentration of silica-containing solutions from 225 mg/L to 600 mg/L SiO2 at comparable operating conditions. Water flux was impacted by silica scaling in both MD and NF processes; however, an induction time was observed before flux decline occurred during MD experiments, which was not observed for NF. Salt rejection during MD was > 99.8% for all solutions tested and was unaffected by scaling, whereas rejection during NF was between 78% and 90% and tended to decrease after scaling. Attempts to clean the fouled membranes for both processes by rinsing with an NaOH solution at pH > 11 were partially effective at restoring water flux but unable to completely remove the silica scale layer.
•Membrane distillation and nanofiltration were used to concentrate silica solutions.•Both processes were impacted by silica scaling.•Silica scaling in membrane distillation was preceded by an induction time.•Silica scaling was accelerated in both processes by Ca2+ ions.•Silica scaling on both membranes was partially reversible following NaOH rinsing (pH>11).
Selective covalent inhibition of kinases by targeting poorly conserved cysteines has proven highly fruitful to date in the development of chemical probes and approved drugs. However, this approach is ...limited to ∼200 kinases possessing such a cysteine near the ATP-binding pocket. Herein, we report a novel approach to achieve selective, irreversible kinase inhibition, by targeting the conserved catalytic lysine residue. We have illustrated our approach by developing selective, covalent PI3Kδ inhibitors that exhibit nanomolar potency in cellular assays, and a duration of action >48 h in CD4+ T cells. Despite conservation of the lysine residue throughout the kinome, the lead compound shows high levels of selectivity over a selection of lipid and protein kinases in biochemical assays, as well as covalent binding to very few off-target proteins in live-cell proteomic studies. We anticipate this approach could offer a general strategy, as an alternative to targeting non-conserved cysteines, for the development of selective covalent kinase inhibitors.
Mesenchymal stromal cells (MSCs) are a subset of progenitor cells that help to promote tissue healing and regeneration through the secretion of various cytokines and growth factors. Although ...technically pluripotent, MSCs in vivo rarely repair damaged tissue through direct differentiation and engraftment.
Augmentation of traditional marrow stimulation techniques with MSCs has been theorized to improve repair tissue quality and defect fill. Clinical trials evaluating this technique are limited but have shown modest improvements compared with isolated marrow stimulation.
Various scaffolds also have been utilized in combination with MSCs to treat focal chondral defects. Although the techniques described are heterogeneous, many have shown promising early clinical outcomes.
Newer techniques involving 3-dimensional bioprinted scaffolds seeded with MSCs allow for the recreation of complex architecture, more closely resembling articular cartilage. These techniques are evolving and have not yet been studied in human clinical trials.
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