Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder.

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity.

An acoustic investigation of the near-surface turbulence on Mars.

The Perseverance rover is carrying out an original acoustic experiment on Mars: the SuperCam microphone records the spherical acoustic waves generated by laser sparks at distances from 2 m to more than 8 m. These N-shaped acoustic waves scatter from the multiple local heterogeneities of the turbulent atmosphere. Therefore, large and random fluctuations of sound travel time and intensity develop as the waves cross the medium. The variances of the travel times and the scintillation index (normalized variance of the sound intensity) are studied within the mathematical formalism of the propagation of spherical acoustic waves through thermal turbulence to infer statistical properties of the Mars atmospheric temperature fluctuation field. The comparison with the theory is made by simplifying assumptions that do not include wind fluctuations and diffraction effects. Two Earth years (about one Martian year) of observations acquired during the maximum convective period (10:00-14:00 Mars local time) show a good agreement between the dataset and the formalism: the travel time variance diverges from the linear Chernov solution exactly where the density of occurrence of the first caustic reaches its maximum. Moreover, on average, waves travel faster than the mean speed of sound due to a fast path effect, which is also observed on Earth. To account for the distribution of turbulent eddies, several power spectra are tested and the best match to observation is obtained with a generalized von Karman spectrum with a shallower slope than the Kolmogorov cascade, ϕ(k)∝(1+k2L2)-4/3. It is associated with an outer scale of turbulence, L, of 11 cm at 2 m above the surface and a standard deviation of 6 K over 9 s for the temperature. These near-surface atmospheric properties are consistent with a weak to moderate wave scattering regime around noon with little saturation. Overall, this study presents an innovative and promising methodology to probe the near-surface atmospheric turbulence on Mars.

Heparanase Blockade as a Novel Dual-Targeting Therapy for COVID-19.

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused over 5 million deaths worldwide. Pneumonia and systemic inflammation contribute to its high mortality. Many viruses use heparan sulfate proteoglycans as coreceptors for viral entry, and heparanase (HPSE) is a known regulator of both viral entry and inflammatory cytokines. We evaluated the heparanase inhibitor Roneparstat, a modified heparin with minimum anticoagulant activity, in pathophysiology and therapy for COVID-19. We found that Roneparstat significantly decreased the infectivity of SARS-CoV-2, SARS-CoV-1, and retroviruses (human T-lymphotropic virus 1 [HTLV-1] and HIV-1) in vitro. Single-cell RNA sequencing (scRNA-seq) analysis of cells from the bronchoalveolar lavage fluid of COVID-19 patients revealed a marked increase in HPSE gene expression in CD68+ macrophages compared to healthy controls. Elevated levels of HPSE expression in macrophages correlated with the severity of COVID-19 and the expression of inflammatory cytokine genes, including IL6, TNF, IL1B, and CCL2. In line with this finding, we found a marked induction of HPSE and numerous inflammatory cytokines in human macrophages challenged with SARS-CoV-2 S1 protein. Treatment with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-mediated inflammatory cytokine release from human macrophages, through disruption of NF-κB signaling. HPSE knockdown in a macrophage cell line also showed diminished inflammatory cytokine production during S1 protein challenge. Taken together, this study provides a proof of concept that heparanase is a target for SARS-CoV-2-mediated pathogenesis and that Roneparstat may serve as a dual-targeted therapy to reduce viral infection and inflammation in COVID-19. IMPORTANCE The complex pathogenesis of COVID-19 consists of two major pathological phases: an initial infection phase elicited by SARS-CoV-2 entry and replication and an inflammation phase that could lead to tissue damage, which can evolve into acute respiratory failure or even death. While the development and deployment of vaccines are ongoing, effective therapy for COVID-19 is still urgently needed. In this study, we explored HPSE blockade with Roneparstat, a phase I clinically tested HPSE inhibitor, in the context of COVID-19 pathogenesis. Treatment with Roneparstat showed wide-spectrum anti-infection activities against SARS-CoV-2, HTLV-1, and HIV-1 in vitro. In addition, HPSE blockade with Roneparstat significantly attenuated SARS-CoV-2 S1 protein-induced inflammatory cytokine release from human macrophages through disruption of NF-κB signaling. Together, this study provides a proof of principle for the use of Roneparstat as a dual-targeting therapy for COVID-19 to decrease viral infection and dampen the proinflammatory immune response mediated by macrophages.

Radically truncated MeCP2 rescues Rett syndrome-like neurological defects.

Heterozygous mutations in the X-linked MECP2 gene cause the neurological disorder Rett syndrome. The methyl-CpG-binding protein 2 (MeCP2) protein is an epigenetic reader whose binding to chromatin primarily depends on 5-methylcytosine. Functionally, MeCP2 has been implicated in several cellular processes on the basis of its reported interaction with more than 40 binding partners, including transcriptional co-repressors (for example, the NCoR/SMRT complex), transcriptional activators, RNA, chromatin remodellers, microRNA-processing proteins and splicing factors. Accordingly, MeCP2 has been cast as a multi-functional hub that integrates diverse processes that are essential in mature neurons. At odds with the concept of broad functionality, missense mutations that cause Rett syndrome are concentrated in two discrete clusters coinciding with interaction sites for partner macromolecules: the methyl-CpG binding domain and the NCoR/SMRT interaction domain. Here we test the hypothesis that the single dominant function of MeCP2 is to physically connect DNA with the NCoR/SMRT complex, by removing almost all amino-acid sequences except the methyl-CpG binding and NCoR/SMRT interaction domains. We find that mice expressing truncated MeCP2 lacking both the N- and C-terminal regions (approximately half of the native protein) are phenotypically near-normal; and those expressing a minimal MeCP2 additionally lacking a central domain survive for over one year with only mild symptoms. This minimal protein is able to prevent or reverse neurological symptoms when introduced into MeCP2-deficient mice by genetic activation or virus-mediated delivery to the brain. Thus, despite evolutionary conservation of the entire MeCP2 protein sequence, the DNA and co-repressor binding domains alone are sufficient to avoid Rett syndrome-like defects and may therefore have therapeutic utility.

Opposing Functions of Heparanase-1 and Heparanase-2 in Cancer Progression.

Heparanase, the sole heparan sulfate (HS)-degrading endoglycosidase, regulates multiple biological activities that enhance tumor growth, metastasis, angiogenesis, and inflammation. Heparanase accomplishes this by degrading HS and thereby regulating the bioavailability of heparin-binding proteins; priming the tumor microenvironment; mediating tumor-host crosstalk; and inducing gene transcription, signaling pathways, exosome formation, and autophagy that together promote tumor cell performance and chemoresistance. By contrast, heparanase-2, a close homolog of heparanase, lacks enzymatic activity, inhibits heparanase activity, and regulates selected genes that promote normal differentiation, endoplasmic reticulum stress, tumor fibrosis, and apoptosis, together resulting in tumor suppression. The emerging premise is that heparanase is a master regulator of the aggressive phenotype of cancer, while heparanase-2 functions as a tumor suppressor.

Seroconversion and outcomes after initial and booster COVID-19 vaccination in adults with hematologic malignancies.

BACKGROUND: Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination. METHODS: The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes. RESULTS: Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection. CONCLUSIONS: Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population. LAY SUMMARY: Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

The VitMin Lab Sandwich-ELISA Assays for Iron and Inflammation Markers Compared Well with Clinical Analyzer Reference-Type Assays in Subsamples of the Nepal National Micronutrient Status Survey.

BACKGROUND: The low cost and small specimen volume of the VitMin Lab ELISA assays for serum ferritin (Fer), soluble transferrin receptor (sTfR), C-reactive protein (CRP), and α-1-acid glycoprotein (AGP) have allowed their application to micronutrient surveys conducted in low-resource countries for ∼2 decades. OBJECTIVES: We conducted a comparison between the ELISA and reference-type assays used in the US NHANES. METHODS: Using the Roche clinical analyzer as a reference, we measured random subsets of the 2016 Nepal National Micronutrient Status Survey (200 serum samples from children aged 6-59 mo; 100 serum samples from nonpregnant women) for Fer, sTfR, CRP, and AGP. We compared the combined data sets with the ELISA survey results using descriptive analyses. RESULTS: The Lin's concordance coefficients between the 2 assays were ≥0.89 except for sTfR (Lin's ρ = 0.58). The median relative difference to the reference was as follows: Fer, -8.5%; sTfR, 71.2%; CRP, -19.5%; and AGP, -8.2%. The percentage of VitMin samples agreeing within ±30% of the reference was as follows: Fer, 88.5%; sTfR, 1.70%; CRP, 74.9%; and AGP, 92.9%. The prevalence of abnormal results was comparable between the 2 assays for Fer, CRP, and AGP, and for sTfR after adjusting to the Roche assay. Continued biannual performance (2007-2019) of the VitMin assays in CDC's external quality assessment program (6 samples/y) demonstrated generally acceptable performance. CONCLUSIONS: Using samples from the Nepal survey, the VitMin ELISA assays produced mostly comparable results to the Roche reference-type assays for Fer, CRP, and AGP. The lack of sTfR assay standardization to a common reference material explains the large systematic difference observed for sTfR, which could be corrected by an adjustment equation pending further validation. This snapshot comparison together with the long-term external quality assessment links the survey data generated by the VitMin Lab to the Roche assays used in NHANES.

Anisotropic spin-orbit torque generation in epitaxial SrIrO3 by symmetry design.

Spin-orbit coupling (SOC), the interaction between the electron spin and the orbital angular momentum, can unlock rich phenomena at interfaces, in particular interconverting spin and charge currents. Conventional heavy metals have been extensively explored due to their strong SOC of conduction electrons. However, spin-orbit effects in classes of materials such as epitaxial 5d-electron transition-metal complex oxides, which also host strong SOC, remain largely unreported. In addition to strong SOC, these complex oxides can also provide the additional tuning knob of epitaxy to control the electronic structure and the engineering of spin-to-charge conversion by crystalline symmetry. Here, we demonstrate room-temperature generation of spin-orbit torque on a ferromagnet with extremely high efficiency via the spin-Hall effect in epitaxial metastable perovskite SrIrO3 We first predict a large intrinsic spin-Hall conductivity in orthorhombic bulk SrIrO3 arising from the Berry curvature in the electronic band structure. By manipulating the intricate interplay between SOC and crystalline symmetry, we control the spin-Hall torque ratio by engineering the tilt of the corner-sharing oxygen octahedra in perovskite SrIrO3 through epitaxial strain. This allows the presence of an anisotropic spin-Hall effect due to a characteristic structural anisotropy in SrIrO3 with orthorhombic symmetry. Our experimental findings demonstrate the heteroepitaxial symmetry design approach to engineer spin-orbit effects. We therefore anticipate that these epitaxial 5d transition-metal oxide thin films can be an ideal building block for low-power spintronics.

Factors associated with anaemia in a nationally representative sample of nonpregnant women of reproductive age in Nepal.

We used cross-sectional data from the 2016 Nepal National Micronutrient Status Survey to evaluate factors associated with anaemia among a nationally representative sample of nonpregnant women 15- 49 years (n = 1, 918). Haemoglobin, biomarkers of iron status and other micronutrients, infection, inflammation, and blood disorders were assessed from venous blood. Soil-transmitted helminth and Helicobacter pylori infections were assessed from stool. Sociodemographic, household, and health characteristics and diet were ascertained by interview. We conducted bivariate analyses between candidate predictors and anaemia (haemoglobin <12.0 g/ dL, altitude- and smoking-adjusted). Candidate predictors that were significant in bivariate models (P < 0.05) were included in the multivariable logistic regression model, accounting for complex sampling design. Anaemia prevalence was 20.2% (95% confidence interval [CI] [17.6, 22.8]). Associated with reduced anaemia odds were living in the Mountain and Hill ecological zones relative to the Terai (adjusted odds ratio [AOR] 0.35, 95% CI [0.21, 0.60] and AOR 0.41, 95% CI [0.29, 0.59], respectively), recent cough (AOR 0.56, 95% CI [0.38, 0.82]), hormonal contraceptive use (AOR 0.58; 95% CI [0.38, 0.88]), ln ferritin (micrograms per litre; AOR 0.43, 95% CI [0.35, 0.54]), and ln retinol binding protein (micrograms per litre; AOR 0.20, 95% CI [0.11, 0.37]). Residing in a house with an earth floor (AOR 1.74, 95% CI [1.18, 2.56]), glucose-6- phosphate dehydrogenase deficiency (AOR 2.44, 95% CI [1.66, 3.60]), and haemoglobinopathies (AOR 6.15, 95% CI [3.09, 12.26]) were associated with increased anaemia odds. Interventions that improve micronutrient status, ensure access to hormonal birth control, and replace dirt floors to reduce infection risk might help reduce anaemia in this population.

Factors associated with anaemia among adolescent boys and girls 10-19 years old in Nepal.

We used data from the 2016 Nepal National Micronutrient Status Survey to evaluate factors associated with anaemia (World Health Organization cut-points using altitude- and smoking-adjusted haemoglobin [Hb]) among nationally representative samples of adolescents 10-19 years. Hb, biomarkers of micronutrients, infection and inflammation were assessed from venous blood. Sociodemographic and household characteristics, dietary diversity, pica and recent morbidity were ascertained by interview. We explored bivariate relationships between candidate predictors and anaemia among boys (N = 967) and girls (N = 1,680). Candidate predictors with P < 0.05 in bivariate analyses were included in sex-specific multivariable logistic regression models. Anaemia prevalence was 20.6% (95% confidence interval [CI] [17.1, 24.1]) among girls and 10.9% (95% CI [8.2, 13.6]) among boys. Among girls, living in the Mountain and Hill ecological zones relative to the Terai (adjusted odds ratio [AOR] 0.28, 95% CI [0.15, 0.52] and AOR 0.42, 95% CI [0.25, 0.73], respectively), ln ferritin (µg/L) (AOR 0.53, 95% CI [0.42, 0.68]) and ln retinol binding protein (RBP) (µmol/L) (AOR 0.08, 95% CI [0.04, 0.16]) were associated with reduced anaemia odds. Older age (age in years AOR 1.19, 95% CI [1.12, 1.27]) and Janajati ethnicity relative to the Muslim ethnicity (AOR 3.04, 95% CI [1.10, 8.36]) were associated with higher anaemia odds. Among boys, ln RBP [µmol/L] (AOR 0.25, 95% CI [0.10, 0.65]) and having consumed flesh foods (AOR 0.57, 95% CI [0.33, 0.99]) were associated with lower anaemia odds. Open defecation (AOR 2.36, 95% CI [1.15, 4.84]) and ln transferrin receptor [mg/L] (AOR 3.21, 95% CI [1.25, 8.23]) were associated with increased anaemia odds. Anaemia among adolescents might be addressed through effective public health policy and programs targeting micronutrient status, diet and sanitation.

Penile Doppler ultrasound study in priapism: A systematic review.

BACKGROUND: Penile Doppler ultrasound (PDU) is suggested to be an alternative to blood gas analysis (BGA) from the corpora cavernosa in differentiating between high- and low-flow priapisms, with limited supportive evidence. AIM: To compare penile Doppler ultrasound study and blood gas analysis in the diagnosis of priapism, through a systematic review of the literature. METHODS: Studies were identified by literature search of Medline, Scopus, Cochrane and ClinicalTrials.Gov. Studies were included if their participants had priapism evaluated by Penile Doppler ultrasound, and reported data on the blood gas analysis or pudendal artery angiography (PAA). Two authors independently extracted the articles using predetermined datasets, including indicators of quality. OUTCOMES: Correlation of penile Doppler ultrasound with blood gas analysis and pudendal artery angiography. RESULTS: Twelve studies were included. Three studies compared Penile Doppler ultrasound to blood gas analysis and pudendal artery angiography. Penile Doppler ultrasound was used as adjunctive to blood gas analysis to differentiate low flow from high flow priapism, guidance for embolization, etiological diagnosis in three studies. Compared to pudendal artery angiography, penile Doppler ultrasound had a sensitivity of 40-100% and a specificity of 73%, to localize vascular injury and anatomical abnormalities (two studies). Penile Doppler ultrasound was also used for the follow-up after the treatment of priapism (two studies). No study reported an impact on functional results or a delay of management due to penile Doppler ultrasound use. CLINICAL TRANSLATION: We reviewed evidence on penile Doppler ultrasound study in priapism. Penile Doppler ultrasound study performance was comparable to blood gas from corpus cavernosum. It is recommended to use doppler as an alternative diagnostic tool. STRENGTHS & LIMITATIONS: Our systematic review had limitations. Firstly, the number of cases in the included studies was small. Secondly, these studies were all retrospective. Lastly, few data were reported with regards to hemodynamic parameters of penile Doppler ultrasound, and the majority of studies did not describe these in detail. CONCLUSIONS: Evidence supports that penile Doppler ultrasound is a reliable way for differentiating high-flow and low-flow priapism. We recommend penile Doppler ultrasound study as an alternative of blood gas analysis from corpus cavernosum, especially when the latter is not available. LEVEL OF EVIDENCE: 3.

Relation between Timing of High-Dose Vitamin A Supplementation and Modified-Relative-Dose-Response Values in Children 12-23 Months in Uganda.

BACKGROUND: High-dose vitamin A (VA) supplements (VAS) can temporarily affect VA status. Hence, micronutrient surveys might need to be timed around VAS campaigns to accurately estimate VA deficiency (VAD) prevalence. Little is known about optimal timing of micronutrient surveys when the modified-relative-dose-response (MRDR) is used as a VA indicator. OBJECTIVES: We evaluated the association between days since the end of a VAS campaign and MRDR values in children aged 12-23 mo in Uganda. METHODS: We pooled data from 2 cross-sectional, population-based surveys in eastern Uganda conducted in 2015-2016 (n = 118 children). We estimated the prevalence of VAD (MRDR ≥0.060). Days since the end of a VAS campaign ("days since VAS") was calculated as the interview date minus the end date of the VAS campaign. The MRDR value was assessed using HPLC. We excluded children whose MRDR values were below the limit of detection (<0.007). We used linear regression to evaluate the association between days since VAS and log-transformed MRDR. In adjusted analyses, we controlled for potential confounders. Statistical analyses accounted for the surveys' complex design. RESULTS: The prevalence of VAD was 5.2% (95% CI: 1.1%, 9.3%). Mean days since VAS was 54.1 d (range 39-68 d). Days since VAS was not associated with log-transformed MRDR in unadjusted analyses ($\hat{\beta } = \ $0.0055; 95% CI: -0.009, 0.020; P = 0.45) or adjusted analyses ($\hat{\beta } = $ -0.0073; 95% CI: -0.024, 0.010; P = 0.39). CONCLUSIONS: MRDR measurement through a nutrition survey began as early as 1.3 mo after the end of a VAS campaign in eastern Uganda. Days since the end of a VAS campaign was not associated with MRDR in Ugandan children aged 12-23 mo. Future studies should consider longitudinal designs and evaluate time since VAS and MRDR in children of different ages and in regions with higher VAD prevalence.

Management of Disastrous Complications of Penile Implant Surgery.

RATIONALE: Penile Prosthesis Implantation (PPI) is the definitive treatment for Erectile Dysfunction not responsive to conservative management strategies. Furthermore, it is a staple of surgical treatment of severe Peyronie's Disease (PD) and phallic reconstruction. Expert implantologists occasionally face disastrous complications of penile implant surgery which can prove to be very challenging. In this article we present a selected number of case reports which exemplify this kind of situations and discuss management strategies while also commenting on plausible aetiologies. PATIENTS' CONCERNS: The first case describes a PPI performed in end-stage fibrotic corpora after multiple instances of implantation/explant. The second and third cases show two diametrically opposed approaches to the management of glans necrosis after PPI in post-radical cystectomy patients. The fourth case describes the history of a diabetic patient suffering from glandular, corporal and urethral necrosis after a complicated PPI procedure. The fifth case reports the surgical treatment of a case of recurring PD due to severe scarring and shrinking of a vascular Dacron patch applied in a previous operation. DIAGNOSIS: Complication diagnosis in all patient was mainly clinical, intra- and postoperative, with Penile Color Doppler Ultrasonography performed when needed in order to demonstrate penile blood flow. INTERVENTIONS: The patients underwent complex surgical procedures that addressed each specific complication. Complex penile implants with fibrosis-related complications, penile prosthesis explant with and without surgical debridement of necrotic areas, penile prosthesis explant with necrotic penile shaft and urethral amputation with perineostomy, and complex corporoplasty with scar tissue excision and patch application with PPI were performed in the five patients. OUTCOMES: Penile anatomy and erectile function with PPI was achieved in 4 out of 5 patients. 1 of 5 patient is scheduled to undergo a total phallic reconstruction procedure at the time of this writing. LESSONS: Management of disastrous complications of penile implant surgery can be very challenging even in expert hands. In-and-out knowledge of possible PPI and PD complications is required to achieve an acceptable outcome. Bettocchi C, Osmonov D, van Renterghem K, et al. Management of Disastrous Complications of Penile Implant Surgery. J Sex Med 2021;18:1145-1157.

Rare-Earth Elements as Natural Tracers for In Situ Remediation of Groundwater.

The utility of rare-earth elements (REEs) as natural geochemical tracers for the analysis of groundwater remediation was examined in several example permeable reactive barriers (PRBs). The PRBs utilize zero-valent iron and organic carbon plus limestone mixtures for contaminant treatment. Zero-valent iron removed REEs from groundwater to below detection levels (2-4 ng/L) and subsequent rebound of REE concentrations in regions down-gradient of the treatment zones was not observed. In addition, REE concentrations within and down-gradient of an organic carbon/limestone PRB were significantly reduced to <1% of influent levels. Thus, REEs are sensitive tracers for evaluating the interaction of groundwater with materials placed in the subsurface for contaminant remediation. Analysis of geochemical tracers for understanding in situ remediation becomes important in situations where down-gradient contaminant concentrations fail to decrease within expected timeframes. The field data indicated that increased solid-phase partitioning of REEs occurred with increasing pH and heavy REEs were preferentially removed compared to light REEs in ZVI systems. In the organic carbon PRB, unexpected negative europium anomalies were observed, revealing new information about redox conditions within the treatment zone. REE concentrations and shale-normalized profiles can be used as natural tracers to better understand in situ technologies for groundwater remediation.

Spliceosome-mediated decay (SMD) regulates expression of nonintronic genes in budding yeast.

We uncovered a novel role for the spliceosome in regulating mRNA expression levels that involves splicing coupled to RNA decay, which we refer to as spliceosome-mediated decay (SMD). Our transcriptome-wide studies identified numerous transcripts that are not known to have introns but are spliced by the spliceosome at canonical splice sites in Saccharomyces cerevisiae. Products of SMD are primarily degraded by the nuclear RNA surveillance machinery. We demonstrate that SMD can significantly down-regulate mRNA levels; splicing at canonical splice sites in the bromodomain factor 2 (BDF2) transcript reduced transcript levels roughly threefold by generating unstable products that are rapidly degraded by the nuclear surveillance machinery. Regulation of BDF2 mRNA levels by SMD requires Bdf1, a functionally redundant Bdf2 paralog that plays a role in recruiting the spliceosome to the BDF2 mRNA. Interestingly, mutating BDF2 5' splice site and branch point consensus sequences partially suppresses the bdf1Δ temperature-sensitive phenotype, suggesting that maintaining proper levels of Bdf2 via SMD is biologically important. We propose that the spliceosome can also repress protein-coding gene expression by promoting nuclear turnover of spliced RNA products and provide an insight for coordinated regulation of Bdf1 and Bdf2 levels in the cell.

An Integrated Infant and Young Child Feeding and Small-Quantity Lipid-based Nutrient Supplementation Program Is Associated with Improved Gross Motor and Communication Scores of Children 6-18 Months in the Democratic Republic of Congo.

OBJECTIVE: To evaluate the impact of an infant, young child feeding practices-small-quantity lipid nutrient supplements (SQ-LNS) intervention on child development scores in children aged 6-18 months in the Katanga Province, Democratic Republic of Congo (DRC). STUDY DESIGN: We analyzed data of 2595 children from 2 health zones in a quasi-experimental design with preimplementation and postimplementation surveys to evaluate program impact on child development scores. Standard care was received in the comparison health zone and the intervention health zone received standard care plus enhanced infant, young child feeding practices with a monthly supply of 28 SQ-LNS sachets for up to 1 year. Program exposure and communication and motor domains of the Ages and Stages questionnaire were collected to assess changes in child development scores. A quasi-intent-to-treat and adjusted difference-in-difference analyses were used to quantify impact of the enhanced compared with the standard package. RESULTS: In adjusted models contrasting endline with baseline, there was a greater relative increase in proportion of children with normal communication (difference-in-difference, +13.7% [95%CI, 7.9-19.6; P < .001] and gross motor scores, +7.4% [95% CI: 1.3-13.5; P < .001]) in the intervention vs comparison health zones. Further, in separate analyses among children of intervention health zone at endline, each additional SQ-LNS distribution was associated with +0.09 (95% CI, 0.03-0.16) z-score unit increase in gross motor scores (P < .01). CONCLUSIONS: The integrated infant, young child feeding practice-SQ-LNS intervention was positively associated with larger relative improvements in measures of child communication and motor development in the Katanga province of DRC.

An Integrated Infant and Young Child Feeding and Micronutrient Powder Intervention Does Not Affect Anemia, Iron Status, or Vitamin A Status among Children Aged 12-23 Months in Eastern Uganda.

BACKGROUND: Micronutrient powders (MNP) can reduce iron deficiency and anemia in children. OBJECTIVE: We evaluated the impact of an integrated infant and young child feeding (IYCF)-MNP intervention on anemia and micronutrient status among children aged 12-23 mo in Eastern Uganda. The intervention focused on MNP distribution, IYCF education, and caregiver behavior change. METHODS: Population-based cross-sectional surveys representative of children aged 12-23 mo in Amuria (intervention) and Soroti (nonintervention) districts were collected in June/July 2015 at baseline (n = 1260) and 12 mo after implementation at endline in 2016 (n = 1490). From pooled capillary blood, we assessed hemoglobin, malaria, ferritin, retinol binding protein (RBP), C-reactive protein, and ɑ1-acid glycoprotein. Ferritin and RBP were regression-adjusted to correct for inflammation. Caregivers reported sociodemographic characteristics and MNP knowledge and practices. Linear regression estimated the difference-in-difference (DiD) effect of MNP on hemoglobin, ferritin, and RBP, and logistic regression estimated DiD effect of MNP on anemia (hemoglobin <11.0 g/dL), iron deficiency (ferritin <12.0 µg/L), iron deficiency anemia (hemoglobin <11.0 g/dL and ferritin <12.0 µg/L), and vitamin A deficiency (VAD; RBP equivalent to <0.70 µmol/L retinol: <0.79 µmol/L at baseline and RBP <0.67 µmol/L at endline). RESULTS: In Amuria, 96% of children had ever consumed MNP versus <1% of children in Soroti. Fifty-four percent of caregivers reported organoleptic changes when MNP were added to foods cooked with soda ash. Adjusting for age, sex, malaria, recent morbidity, and household-level factors, the intervention was associated with -0.83 g/dL lower hemoglobin (95% CI, -1.36, -0.30 g/dL; P = 0.003) but not with anemia, ferritin, iron deficiency, iron deficiency anemia, RBP, or VAD. CONCLUSIONS: Despite high program fidelity, the intervention was associated with reduced hemoglobin concentrations but not with change in anemia or micronutrient status among children aged 12-23 mo in Eastern Uganda. Contextual factors, such as cooking with soda ash, might explain the lack of effectiveness.

Age, Ethnicity, Glucose-6-Phosphate Dehydrogenase Deficiency, Micronutrient Powder Intake, and Biomarkers of Micronutrient Status, Infection, and Inflammation Are Associated with Anemia Among Children 6-59 Months in Nepal.

BACKGROUND: Anemia is a major concern for children in Nepal; however, little is known about context-specific causes of anemia. OBJECTIVE: We used cross-sectional data from the 2016 Nepal National Micronutrient Status Survey to evaluate factors associated with anemia in a nationally representative, population-based sample of children 6-59 mo (n = 1367). METHODS: Hemoglobin, biomarkers of iron status and other micronutrients, infection, inflammation, and blood disorders were assessed from venous blood samples. Soil-transmitted helminth (STH) and Helicobacter pylori infections were assessed from stool. Anthropometry was measured with standard procedures. Sociodemographic and household characteristics, diet, micronutrient powder (MNP) intake, pica, and morbidity recall were ascertained by caregiver interview. Multivariable logistic regression that accounted for complex sampling design, determined predictors of anemia (hemoglobin <11.0 g/dL, altitude adjusted); candidate predictors were variables with P < 0.05 in bivariate models. RESULTS: Anemia prevalence was 18.6% (95% CI: 15.8, 21.4). MNP intake [adjusted OR (AOR): 0.25, 95% CI: 0.07, 0.86], log (ln) ferritin (µg/L) (AOR: 0.49, 95% CI: 0.38, 0.64), and ln RBP (µmol/L) (AOR: 0.42, 95% CI: 0.18, 0.95) were associated with reduced odds of anemia. Younger age (6-23 mo compared with 24-59 mo; AOR: 2.29, 95% CI: 1.52, 3.46), other Terai ethnicities (AOR: 2.59, 95% CI: 1.25, 5.35) and Muslim ethnicities (AOR: 3.15, 95% CI: 1.30, 7.65) relative to Brahmin/Chhetri ethnicities, recent fever (AOR: 1.68, 95% CI: 1.08, 2.59), ln C-reactive protein (mg/L) (AOR: 1.23, 95% CI: 1.03, 1.45), and glucose-6-phosphate dehydrogenase deficiency (AOR: 2.84, 95% CI: 1.88, 4.30) were associated with increased odds of anemia. CONCLUSION: Both nonmodifiable and potentially modifiable factors were associated with anemia. Thus some but not all anemia might be addressed through effective public health policy, programs, and delivery of nutrition and infection prevention and control.

Proteoglycan Chemical Diversity Drives Multifunctional Cell Regulation and Therapeutics.

The extracellular matrix (ECM) constitutes a highly dynamic three-dimensional structural network comprised of macromolecules, such as proteoglycans/glycosaminoglycans (PGs/GAGs), collagens, laminins, fibronectin, elastin, other glycoproteins and proteinases. In recent years, the field of PGs has expanded rapidly. Due to their high structural complexity and heterogeneity, PGs mediate several homeostatic and pathological processes. PGs consist of a protein core and one or more covalently attached GAG chains, which provide the protein cores with the ability to interact with several proteins. The GAG building blocks of PGs significantly influence the chemical and functional properties of PGs. The primary goal of this comprehensive review is to summarize major achievements and paradigm-shifting discoveries made on the PG/GAG chemistry-biology axis, focusing on structural variability, structure-function relationships, metabolic, molecular, and epigenetic mechanisms underlying their synthesis. Recent insights related to exosome biogenesis, degradation, and cell signaling, their status as diagnostic tools and potential pharmacological targets in diseases as well as current applications in nanotechnology and biotechnology are addressed. Moreover, issues related to docking studies, molecular modeling, GAG/PG interaction networks, and their integration are discussed.

Influence of the Multi-Mission Radioisotope Thermoelectric Generator (MMRTG) on the local atmospheric environment.

A survey around a recently-fueled MMRTG in the terrestrial atmosphere finds a warm air plume with a characteristic updraft velocity of ~1 m/s and a temperature rise of ~4 â€‹K. Additionally, a roughly hundredfold enhancement in ion density to ~70,000/cm3 in the vicinity (<~1 â€‹m) of the generator was observed: air electrical conductivity was measured to be ~10-13 â€‹S/m. No evidence of ozone production was detected. These observations inform the electrical charging environment and possible local perturbation to meteorological measurements on Mars or Titan on MMRTG-powered landers or rovers. On Mars, the effects of any electrical conductivity enhancement are likely small, but on Titan they may be significant.