Commonly disrupted pathways in brain and kidney in a pig model of systemic endotoxemia.

Sepsis is a life-threatening state that arises due to a hyperactive inflammatory response stimulated by infection and rarely other insults (e.g., non-infections tissue injury). Although changes in several proinflammatory cytokines and signals are documented in humans and small animal models, far less is known about responses within affected tissues of large animal models. We sought to understand the changes that occur during the initial stages of inflammation by administering intravenous lipopolysaccharide (LPS) to Yorkshire pigs and assessing transcriptomic alterations in the brain, kidney, and whole blood. Robust transcriptional alterations were found in the brain, with upregulated responses enriched in inflammatory pathways and downregulated responses enriched in tight junction and blood vessel functions. Comparison of the inflammatory response in the pig brain to a similar mouse model demonstrated some overlapping changes but also numerous differences, including oppositely dysregulated genes between species. Substantial changes also occurred in the kidneys following LPS with several enriched upregulated pathways (cytokines, lipids, unfolded protein response, etc.) and downregulated gene sets (tube morphogenesis, glomerulus development, GTPase signal transduction, etc.). We also found significant dysregulation of genes in whole blood that fell into several gene ontology categories (cytokines, cell cycle, neutrophil degranulation, etc.). We observed a strong correlation between the brain and kidney responses, with significantly shared upregulated pathways (cytokine signaling, cell death, VEGFA pathways) and downregulated pathways (vasculature and RAC1 GTPases). In summary, we have identified a core set of shared genes and pathways in a pig model of systemic inflammation.

Atopic dermatitis (eczema) guidelines: 2023 American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters GRADE- and Institute of Medicine-based recommendations.

BACKGROUND: Guidance addressing atopic dermatitis (AD) management, last issued in 2012 by the American Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force, requires updating as a result of new treatments and improved guideline and evidence synthesis methodology. OBJECTIVE: To produce evidence-based guidelines that support patients, clinicians, and other decision-makers in the optimal treatment of AD. METHODS: A multidisciplinary guideline panel consisting of patients and caregivers, AD experts (dermatology and allergy/immunology), primary care practitioners (family medicine, pediatrics, internal medicine), and allied health professionals (psychology, pharmacy, nursing) convened, prioritized equity, diversity, and inclusiveness, and implemented management strategies to minimize influence of conflicts of interest. The Evidence in Allergy Group supported guideline development by performing systematic evidence reviews, facilitating guideline processes, and holding focus groups with patient and family partners. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach informed rating the certainty of evidence and strength of recommendations. Evidence-to-decision frameworks, subjected to public comment, translated evidence to recommendations using trustworthy guideline principles. RESULTS: The panel agreed on 25 recommendations to gain and maintain control of AD for patients with mild, moderate, and severe AD. The eAppendix provides practical information and implementation considerations in 1-2 page patient-friendly handouts. CONCLUSION: These evidence-based recommendations address optimal use of (1) topical treatments (barrier moisturization devices, corticosteroids, calcineurin inhibitors, PDE4 inhibitors [crisaborole], topical JAK inhibitors, occlusive [wet wrap] therapy, adjunctive antimicrobials, application frequency, maintenance therapy), (2) dilute bleach baths, (3) dietary avoidance/elimination, (4) allergen immunotherapy, and (5) systemic treatments (biologics/monoclonal antibodies, small molecule immunosuppressants [cyclosporine, methotrexate, azathioprine, mycophenolate, JAK inhibitors], and systemic corticosteroids) and UV phototherapy (light therapy).

Allergen immunotherapy for atopic dermatitis: Systematic review and meta-analysis of benefits and harms.

BACKGROUND: Atopic dermatitis (AD, eczema) is driven by a combination of skin barrier defects, immune dysregulation, and extrinsic stimuli such as allergens, irritants, and microbes. The role of environmental allergens (aeroallergens) in triggering AD remains unclear. OBJECTIVE: We systematically synthesized evidence regarding the benefits and harms of allergen immunotherapy (AIT) for AD. METHODS: As part of the 2022 American Academy of Allergy, Asthma & Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters AD Guideline update, we searched the MEDLINE, EMBASE, CENTRAL, CINAHL, LILACS, Global Resource for Eczema Trials, and Web of Science databases from inception to December 2021 for randomized controlled trials comparing subcutaneous immunotherapy (SCIT), sublingual immunotherapy (SLIT), and/or no AIT (placebo or standard care) for guideline panel-defined patient-important outcomes: AD severity, itch, AD-related quality of life (QoL), flares, and adverse events. Raters independently screened, extracted data, and assessed risk of bias in duplicate. We synthesized intervention effects using frequentist and Bayesian random-effects models. The GRADE approach determined the quality of evidence. RESULTS: Twenty-three randomized controlled trials including 1957 adult and pediatric patients sensitized primarily to house dust mite showed that add-on SCIT and SLIT have similar relative and absolute effects and likely result in important improvements in AD severity, defined as a 50% reduction in SCORing Atopic Dermatitis (risk ratio [95% confidence interval] 1.53 [1.31-1.78]; 26% vs 40%, absolute difference 14%) and QoL, defined as an improvement in Dermatology Life Quality Index by 4 points or more (risk ratio [95% confidence interval] 1.44 [1.03-2.01]; 39% vs 56%, absolute difference 17%; both outcomes moderate certainty). Both routes of AIT increased adverse events (risk ratio [95% confidence interval] 1.61 [1.44-1.79]; 66% with SCIT vs 41% with placebo; 13% with SLIT vs 8% with placebo; high certainty). AIT's effect on sleep disturbance and eczema flares was very uncertain. Subgroup and sensitivity analyses were consistent with the main findings. CONCLUSIONS: SCIT and SLIT to aeroallergens, particularly house dust mite, can similarly and importantly improve AD severity and QoL. SCIT increases adverse effects more than SLIT. These findings support a multidisciplinary and shared decision-making approach to optimally managing AD.

Systemic treatments for atopic dermatitis (eczema): Systematic review and network meta-analysis of randomized trials.

BACKGROUND: Atopic dermatitis (AD) is an inflammatory skin condition with multiple systemic treatments and uncertainty regarding their comparative impact on AD outcomes. OBJECTIVE: We sought to systematically synthesize the benefits and harms of AD systemic treatments. METHODS: For the 2023 American Academy of Allergy, Asthma & Immunology and American College of Allergy, Asthma, and Immunology Joint Task Force on Practice Parameters AD guidelines, we searched MEDLINE, EMBASE, CENTRAL, Web of Science, and GREAT databases from inception to November 29, 2022, for randomized trials addressing systemic treatments and phototherapy for AD. Paired reviewers independently screened records, extracted data, and assessed risk of bias. Random-effects network meta-analyses addressed AD severity, itch, sleep, AD-related quality of life, flares, and harms. The Grading of Recommendations Assessment, Development and Evaluation approach informed certainty of evidence ratings. This review is registered in the Open Science Framework (https://osf.io/e5sna). RESULTS: The 149 included trials (28,686 patients with moderate-to-severe AD) evaluated 75 interventions. With high-certainty evidence, high-dose upadacitinib was among the most effective for 5 of 6 patient-important outcomes; high-dose abrocitinib and low-dose upadacitinib were among the most effective for 2 outcomes. These Janus kinase inhibitors were among the most harmful in increasing adverse events. With high-certainty evidence, dupilumab, lebrikizumab, and tralokinumab were of intermediate effectiveness and among the safest, modestly increasing conjunctivitis. Low-dose baricitinib was among the least effective. Efficacy and safety of azathioprine, oral corticosteroids, cyclosporine, methotrexate, mycophenolate, phototherapy, and many novel agents are less certain. CONCLUSIONS: Among individuals with moderate-to-severe AD, high-certainty evidence demonstrates that high-dose upadacitinib is among the most effective in addressing multiple patient-important outcomes, but also is among the most harmful. High-dose abrocitinib and low-dose upadacitinib are effective, but also among the most harmful. Dupilumab, lebrikizumab, and tralokinumab are of intermediate effectiveness and have favorable safety.

Threshold-Responsive Colorimetric Sensing System for the Continuous Monitoring of Gases.

Colorimetric sensors are widely used because of their inherent advantages including accuracy, rapid response, ease-of-use, and low costs; however, they usually lack reusability, which precludes the continuous use of a single sensor. We have developed a threshold-responsive colorimetric system that enables repeated analyte measurements by a single colorimetric sensor. The threshold responsive algorithm automatically adjusts the sensor exposure time to the analyte and measurement frequency according to the sensor response. The system registers the colorimetric sensor signal change rate, prevents the colorimetric sensor from reaching saturation, and allows the sensor to fully regenerate before the next measurement is started. The system also addresses issues common to colorimetric sensors, including the response time and range of detection. We demonstrate the benefits and feasibility of this novel system, using colorimetric sensors for ammonia and carbon dioxide gases for continuous monitoring of up to (at least) 60 detection cycles without signs of analytical performance degradation of the sensors.

Correlating the Role of Nanofillers with Active Layer Properties and Performance of Thin-Film Nanocomposite Membranes.

Thin-film nanocomposite (TFN) membranes are emerging water-purification membranes that could provide enhanced water permeance with similar solute removal over traditional thin-film composite (TFC) membranes. However, the effects of nanofiller incorporation on active layer physico-chemical properties have not been comprehensively studied. Accordingly, we aimed to understand the correlation between nanofillers, active layer physico-chemical properties, and membrane performance by investigating whether observed performance differences between TFN and control TFC membranes correlated with observed differences in physico-chemical properties. The effects of nanofiller loading, surface area, and size on membrane performance, along with active layer physico-chemical properties, were characterized in TFN membranes incorporated with Linde Type A (LTA) zeolite and zeolitic imidazole framework-8 (ZIF-8). Results show that nanofiller incorporation up to ~0.15 wt% resulted in higher water permeance and unchanged salt rejection, above which salt rejection decreased 0.9-25.6% and 26.1-48.3% for LTA-TFN and ZIF-8-TFN membranes, respectively. Observed changes in active layer physico-chemical properties were generally unsubstantial and did not explain observed changes in TFN membrane performance. Therefore, increased water permeance in TFN membranes could be due to preferential water transport through porous structures of nanofillers or along polymer-nanofiller interfaces. These findings offer new insights into the development of high-performance TFN membranes for water/ion separations.

The TALE never ends: A comprehensive overview of the role of PBX1, a TALE transcription factor, in human developmental defects.

PBX1 is a highly conserved atypical homeodomain transcription factor (TF) belonging to the TALE (three amino acid loop extension) family. Dimerized with other TALE proteins, it can interact with numerous partners and reach dozens of regulating sequences, suggesting its role as a pioneer factor. PBX1 is expressed throughout the embryonic stages (as early as the blastula stage) in vertebrates. In human, PBX1 germline variations are linked to syndromic renal anomalies (CAKUTHED). In this review, we summarized available data on PBX1 functions, PBX1-deficient animal models, and PBX1 germline variations in humans. Two types of genetic alterations were identified in PBX1 gene. PBX1 missense variations generate a severe phenotype including lung hypoplasia, cardiac malformations, and sexual development defects (DSDs). Conversely, truncating variants generate milder phenotypes (mainly cryptorchidism and deafness). We suggest that defects in PBX1 interactions with various partners, including proteins from the HOX (HOXA7, HOXA10, etc.), WNT (WNT9B, WNT3), and Polycomb (BMI1, EED) families are responsible for abnormal proliferation and differentiation of the embryonic mesenchyme. These alterations could explain most of the defects observed in humans. However, some phenotype variability (especially DSDs) remains poorly understood. Further studies are needed to explore the TALE family in greater depth.

Pseudodicentric Chromosome Originating from an X-Autosome Translocation in a Male Patient with Cryptozoospermia.

Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies are validated genetic factors leading to spermatogenic quantitative defects, with a frequency depending on the severity of the phenotype. Among the structural chromosomal rearrangements, dicentric chromosomes are generally observed in robertsonian translocations or in cases of Y chromosome isodicentrics. In X-autosome translocations, male carriers are generally infertile, regardless of the position of the breakpoint, due to interrupted spermatogenesis. We report an infertile man bearing an unusual balanced (X;22) translocation, with a centromeric X breakpoint generating a derivative pseudodicentric chromosome psu dic(22;X). Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome. The likely cause of the reproductive phenotype of the patient is discussed based on meiotic chromosomal conformation.

Bleach baths for atopic dermatitis: A systematic review and meta-analysis including unpublished data, Bayesian interpretation, and GRADE.

BACKGROUND: Bleach bathing is frequently recommended to treat atopic dermatitis (AD), but its efficacy and safety are uncertain. OBJECTIVE: To systematically synthesize randomized controlled trials (RCTs) addressing bleach baths for AD. METHODS: We searched MEDLINE, EMBASE, CENTRAL, and GREAT from inception to December 29, 2021, for RCTs assigning patients with AD to bleach vs no bleach baths. Paired reviewers independently and in duplicate screened records, extracted data, and assessed risk of bias (Cochrane version 2) and GRADE quality of evidence. We obtained unpublished data, harmonized individual patient data and did Frequentist and Bayesian random-effects meta-analyses. RESULTS: There were 10 RCTs that enrolled 307 participants (median of mean age 7.2 years, Eczema Area Severity Index baseline mean of means 27.57 [median SD, 10.74]) for a median of 6 weeks (range, 4-10). We confirmed that other trials registered globally were terminated. Bleach baths probably improve AD severity (22% vs 32% improved Eczema Area Severity Index by 50% [ratio of means 0.78, 95% credible interval 0.59-0.99]; moderate certainty) and may slightly reduce skin Staphylococcal aureus colonization (risk ratio, 0.89 [95% confidence interval, 0.73-1.09]; low certainty). Adverse events, mostly dry skin and irritation, along with itch, patient-reported disease severity, sleep quality, quality of life, and risk of AD flares were not clearly different between groups and of low to very low certainty. CONCLUSION: In patients with moderate-to-severe AD, bleach baths probably improve clinician-reported severity by a relative 22%. One in 10 will likely improve severity by 50%. Changes in other patient-important outcomes are uncertain. These findings support optimal eczema care and the need for additional large clinical trials. TRIAL REGISTRATION: PROSPERO Identifier: CRD42021238486.

Terminal 6q deletions cause brain malformations, a phenotype mimicking heterozygous DLL1 pathogenic variants: A multicenter retrospective case series.

OBJECTIVE: Terminal 6q deletion is a rare genetic condition associated with a neurodevelopmental disorder characterized by intellectual disability and structural brain anomalies. Interestingly, a similar phenotype is observed in patients harboring pathogenic variants in the DLL1 gene. Our study aimed to further characterize the prenatal phenotype of this syndrome as well as to attempt to establish phenotype-genotype correlations. METHOD: We collected ultrasound findings from 22 fetuses diagnosed with a pure 6qter deletion. We reviewed the literature and compared our 22 cases with 14 fetuses previously reported as well as with patients with heterozygous DLL1 pathogenic variants. RESULTS: Brain structural alterations were observed in all fetuses. The most common findings (>70%) were cerebellar hypoplasia, ventriculomegaly, and corpus callosum abnormalities. Gyration abnormalities were observed in 46% of cases. Occasional findings included cerebral heterotopia, aqueductal stenosis, vertebral malformations, dysmorphic features, and kidney abnormalities. CONCLUSION: This is the first series of fetuses diagnosed with pure terminal 6q deletion. Based on our findings, we emphasize the prenatal sonographic anomalies, which may suggest the syndrome. Furthermore, this study highlights the importance of chromosomal microarray analysis to search for submicroscopic deletions of the 6q27 region involving the DLL1 gene in fetuses with these malformations.

Multicolor-FISH Characterization of a Prenatal Mosaicism for a Chromosomal Rearrangement Undetected by Molecular Cytogenetics.

Fetal mosaicism for chromosomal rearrangements remains a challenge to diagnose, even in the era of whole-genome sequencing. We present here a case of fetal mosaicism for a chromosomal rearrangement explored in amniocytes and fetal muscle, consisting of a major cell population (95%) with partial monosomy 4q and a minor population (5%) with additional material replacing the 4qter deleted segment. Molecular techniques (MLPA, array-CGH) failed to assess the origin of this material. Only multicolor-FISH identified the additional segment on chromosome 4 as derived from chromosome 17. Due to the poor prognosis, the couple chose to terminate the pregnancy. Because of low-level mosaicism, chromosomal microarray analysis (CMA), now considered as first-tier prenatal genetic analysis, did not allow the identification of the minor cell line. In case of large CNVs (>5 Mb) detected by CMA, karyotyping may be considered to elucidate the mechanism of the underlying rearrangement and eliminate mosaicism.

Pathogenic variants in KCNQ2 cause intellectual deficiency without epilepsy: Broadening the phenotypic spectrum of a potassium channelopathy.

High-throughput sequencing (HTS) improved the molecular diagnosis in individuals with intellectual deficiency (ID) and helped to broaden the phenotype of previously known disease-causing genes. We report herein four unrelated patients with isolated ID, carriers of a likely pathogenic variant in KCNQ2, a gene usually implicated in benign familial neonatal seizures (BFNS) or early onset epileptic encephalopathy (EOEE). Patients were diagnosed by targeted HTS or exome sequencing. Pathogenicity of the variants was assessed by multiple in silico tools. Patients' ID ranged from mild to severe with predominance of speech disturbance and autistic features. Three of the four variants disrupted the same amino acid. Compiling all the pathogenic variants previously reported, we observed a strong overlap between variants causing EOEE, isolated ID, and BFNS and an important intra-familial phenotypic variability, although missense variants in the voltage-sensing domain and the pore are significantly associated to EOEE (p < 0.01, Fisher test). Thus, pathogenic variants in KCNQ2 can be associated with isolated ID. We did not highlight strong related genotype-phenotype correlations in KCNQ2-related disorders. A second genetic hit, a burden of rare variants, or other extrinsic factors may explain such a phenotypic variability. However, it is of interest to study encephalopathy genes in non-epileptic ID patients.

Genetic kinship and admixture in Iron Age Scytho-Siberians.

Scythians are known from written sources as horse-riding nomadic peoples who dominated the Eurasian steppe throughout the Iron Age. However, their origins and the exact nature of their social organization remain debated. Three hypotheses prevail regarding their origins that can be summarized as a "western origin", an "eastern origin" and a "multi-regional origin". In this work, we first aimed to address the question of the familial and social organization of some Scythian groups (Scytho-Siberians) by testing genetic kinship and, second, to add new elements on their origins through phylogeographical analyses. Twenty-eight Scythian individuals from 5 archeological sites in the Tuva Republic (Russia) were analyzed using autosomal Short Tandem Repeats (STR), Y-STR and Y-SNP typing as well as whole mitochondrial (mtDNA) genome sequencing. Familial relationships were assessed using the Likelihood Ratio (LR) method. Thirteen of the 28 individuals tested were linked by first-degree relationships. When related, the individuals were buried together, except for one adult woman, buried separately from her mother and young sister. Y-chromosome analysis revealed a burial pattern linked to paternal lineages, with men bearing closely related Y-haplotypes buried on the same sites. Inversely, various mtDNA lineages can be found on each site. Y-chromosomal and mtDNA haplogroups were almost equally distributed between Western and Eastern Eurasian haplogroups. These results suggest that Siberian Scythians were organized in patrilocal and patrilineal societies with burial practices linked to both kinship and paternal lineages. It also appears that the group analyzed shared a greater genetic link with Asian populations than Western Scythians did.

Pseudodicentric Chromosome Originating from Autosomes 9 and 21 in a Male Patient with Oligozoospermia.

Genetic factors are responsible for 15% of male infertility conditions. Numerical and structural chromosomal anomalies (related to the Y chromosome or to the autosomes) are validated genetic factors leading to spermatogenic quantitative defects with a frequency depending on the severity of the phenotype. The most frequent structural chromosomal rearrangements of autosomes are translocations and inversions, whereas dicentric chromosomes involving autosomes are rare. We report a man bearing a pseudodicentric chromosome (9;21) and presenting with oligozoospermia. Extensive cytogenetic analyses were necessary to determine the precise nature of the derivative chromosome and to discount the presence of interstitial telomeric sequences. Defects in spermatogenesis and abnormal segregation at meiosis for existing spermatozoa are proposed and are the likely cause of the reproductive phenotype of the patient.

Bardet-Biedl syndrome: Antenatal presentation of forty-five fetuses with biallelic pathogenic variants in known Bardet-Biedl syndrome genes.

Bardet-Biedl syndrome (BBS) is an emblematic ciliopathy associated with retinal dystrophy, obesity, postaxial polydactyly, learning disabilities, hypogonadism and renal dysfunction. Before birth, enlarged/cystic kidneys as well as polydactyly are the hallmark signs of BBS to consider in absence of familial history. However, these findings are not specific to BBS, raising the problem of differential diagnoses and prognosis. Molecular diagnosis during pregnancies remains a timely challenge for this heterogeneous disease (22 known genes). We report here the largest cohort of BBS fetuses to better characterize the antenatal presentation. Prenatal ultrasound (US) and/or autopsy data from 74 fetuses with putative BBS diagnosis were collected out of which molecular diagnosis was established in 51 cases, mainly in BBS genes (45 cases) following the classical gene distribution, but also in other ciliopathy genes (6 cases). Based on this, an updated diagnostic decision tree is proposed. No genotype/phenotype correlation could be established but postaxial polydactyly (82%) and renal cysts (78%) were the most prevalent symptoms. However, autopsy revealed polydactyly that was missed by prenatal US in 55% of the cases. Polydactyly must be carefully looked for in pregnancies with apparently isolated renal anomalies in fetuses.

Prenatal diagnosis of focal dermal hypoplasia: Report of three fetuses and review of the literature.

Focal dermal hypoplasia (FDH) is a rare syndrome characterized by pleiotropic features knowing to involve mostly skin and limbs. Although FDH has been described in children and adults, the cardinal signs of the fetal phenotype are not straightforward impacting the quality of the prenatal diagnosis. We describe in depth the ultrasound, radiological, macroscopical, and histological phenotype of three female fetuses with a severe form of FDH, propose a review of the literature and an attempt to delineate minimal and cardinal signs for FDH diagnosis. This report confirms the variability of FDH phenotype, highlights unreported FDH features, and allows delineating evocative clinical associations for prenatal diagnosis, namely intrauterine growth retardation, limbs malformations, anterior wall/diaphragm defects, and eye anomalies. © 2016 Wiley Periodicals, Inc.

Latex barrier thin film formation on porous substrates.

Here we present the formation of thin layers of barrier polymers onto mesoporous and macroporous substrates via dip coating of latex solutions. We investigated four commercially available latex solutions: polytetrafluoroethylene (PTFE), perfluoroalkoxy fluorothermoplastic (PFA), polyvinylidene chloride (PVDC), and polyolefin-based latex (Hypod). We examined the latex film formation on porous polymeric and ceramic substrates with a broad range of pore sizes from 10 to 200 nm. Our results show that both characteristics of the latex solution [glass transition temperature (Tg), particle size, and crystallinity] and the characteristics of the porous substrate (pore size and hydrophobicity) impact the film formation. We confirmed the defect-free, barrier nature of our latex thin films through scanning electron microscopy (SEM), atomic force microscopy (AFM), and hydraulically driven water permeation tests. Additionally, we found that latex concentration (not dipping time) is the most important parameter determining ultimate latex film thickness. We obtained defect-free films from PVDC and Hypod, which are "soft" polymers (Tg < room temperature), on mesoporous substrates under the conditions of slow evaporation rate of the solvent from these latex solutions. PTFE and PFA, which are "hard" polymers (Tg > room temperature), did not form continuous films on porous substrates.

Designing metallic glass matrix composites with high toughness and tensile ductility.

The selection and design of modern high-performance structural engineering materials is driven by optimizing combinations of mechanical properties such as strength, ductility, toughness, elasticity and requirements for predictable and graceful (non-catastrophic) failure in service. Highly processable bulk metallic glasses (BMGs) are a new class of engineering materials and have attracted significant technological interest. Although many BMGs exhibit high strength and show substantial fracture toughness, they lack ductility and fail in an apparently brittle manner in unconstrained loading geometries. For instance, some BMGs exhibit significant plastic deformation in compression or bending tests, but all exhibit negligible plasticity (<0.5% strain) in uniaxial tension. To overcome brittle failure in tension, BMG-matrix composites have been introduced. The inhomogeneous microstructure with isolated dendrites in a BMG matrix stabilizes the glass against the catastrophic failure associated with unlimited extension of a shear band and results in enhanced global plasticity and more graceful failure. Tensile strengths of approximately 1 GPa, tensile ductility of approximately 2-3 per cent, and an enhanced mode I fracture toughness of K(1C) approximately 40 MPa m(1/2) were reported. Building on this approach, we have developed 'designed composites' by matching fundamental mechanical and microstructural length scales. Here, we report titanium-zirconium-based BMG composites with room-temperature tensile ductility exceeding 10 per cent, yield strengths of 1.2-1.5 GPa, K(1C) up to approximately 170 MPa m(1/2), and fracture energies for crack propagation as high as G(1C) approximately 340 kJ m(-2). The K(1C) and G(1C) values equal or surpass those achievable in the toughest titanium or steel alloys, placing BMG composites among the toughest known materials.

Functional Assessment of a New PBX1 Variant in a 46,XY Fetus with Severe Syndromic Difference of Sexual Development through CRISPR-Cas9 Gene Editing.

Sexual development is a complex process relying on numerous genes. Disruptions in some of these genes are known to cause differences of sexual development (DSDs). Advances in genome sequencing allowed the discovery of new genes implicated in sexual development, such as PBX1. We present here a fetus with a new PBX1 NM_002585.3: c.320G>A,p.(Arg107Gln) variant, presenting with severe DSD along with renal and lung malformations. Using CRISPR-Cas9 gene editing on HEK293T cells, we generated a KD cell line for PBX1. The KD cell line showed reduced proliferation and adhesion properties compared with HEK293T cells. HEK293T and KD cells were then transfected plasmids coding either PBX1 WT or PBX1-320G>A (mutant). WT or mutant PBX1 overexpression rescued cell proliferation in both cell lines. RNA-seq analyses showed less than 30 differentially expressed genes, in ectopic mutant-PBX1-expressing cells compared with WT-PBX1. Among them, U2AF1, encoding a splicing factor subunit, is an interesting candidate. Overall, mutant PBX1 seems to have modest effects compared with WT PBX1 in our model. However, the recurrence of PBX1 Arg107 substitution in patients with closely related phenotypes calls for its impact in human diseases. Further functional studies are needed to explore its effects on cellular metabolism.

Zwitterionic Copolymers for Anti-Scaling Applications in Simulated Spaceflight Wastewater Scenarios.

Water reclamation in spaceflight applications, such as those encountered on the International Space Station (ISS), requires complex engineering solutions to ensure maximum water recovery. Current vapor compression distillation (VCD) technologies are effective but produce highly concentrated brines and often cause scaling within a separation system. This work evaluates initial steps toward integrating pervaporation, a membrane separation process, as a brine management strategy for ISS wastewaters. Pervaporation performs separations driven by a chemical potential difference across the membrane created by either a sweep gas or a vacuum pull. Pervaporation membranes, as with most membrane processes, can be subject to scaling. Therefore, this work studies the anti-scaling properties of zwitterions (polymeric molecules with covalently tethered positive and negative ions) coated onto sulfonated pentablock terpolymer block polymer (Nexar) pervaporation membrane surfaces. We report a method for applying zwitterions to the surface of pervaporation membranes and the effect on performance parameters such as flux and scaling resistance. Membranes with zwitterions had up to 53% reduction in permeance but reduced scaling. The highest amount of scaling occurred in the samples exposed to calcium chloride, and uncoated membranes had weight percent increases as high as 1617 ± 241%, whereas zwitterion-coated membranes experienced only about 317 ± 87% weight increase in the presence of the same scalant.