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Aim: Pregnancy loss (abortus) is defined as loss of fetal cardiac beat or expulsion of pregnancy material before 20 weeks.It has many causes such as chromosomal abnormalities, uterine anomalies, infections, and unknown causes. Vitamin D has become one of the new topics of research in many medical fields, as it has relations with other diseases besides bone diseases. In some studies of recurrent pregnancy loss, a low vitamin D level was found. In our study, vitamin D levels were measured in the first-trimester pregnancy loss and normal pregnancy group. Methods: Patients, single pregnancies with a positive fetal heartbeat, who applied to the pregnant outpatient clinic for the first examination of pregnancy were included in the study, and vitamin D levels were measured at this time. The patients were followed up to the 12th gestational week using the hospital automation system. The groups of normal pregnancy and abortus groups were determined. 25-hydroxy (25-OH) vitamin D levels between 2-96 ng/ml can be detected, while over 30 ng/ml is sufficient, 20-29.99 ng/ml is insufficient, and

Water flowing under ice sheets and glaciers can have a strong influence on ice dynamics, particularly through pressure changes, suggesting that a comprehensive ice sheet model should include the effect of basal hydrology. Modeling subglacial hydrology remains a challenge, however, mainly due to the range of spatial and temporal scales involved – from subglacial channels to vast subglacial lakes. Additionally, networks of subglacial drainage channels dynamically evolve over time. To address some of these challenges, we have developed an adaptive mesh refinement (AMR) model based on the Chombo software framework. We extend the model proposed by Sommers et al. (2018) with a small but significant change to accommodate the transition from unresolved to resolved flow features. We handle the strong nonlinearities present in the equations by resorting to an efficient nonlinear full approximation scheme multigrid (FAS-MG) algorithm. We outline the details of the algorithm and present convergence analysis results demonstrating its good performance. Additionally, we present results validating our approach, using test cases from the Subglacial Hydrology Model Intercomparison Project (SHMIP) (de Fleurian et al., 2018). We finish by presenting a more complex, 100 km-by-100 km synthetic test case with peaks and valleys that we use to investigate the effective pressure distribution as the number of AMR levels increases. These preliminary results suggest that a minimum spatial resolution is needed to properly capture channel features, but additional work is required to precisely quantify this and its impact on accurately modeling the coupled ice sheet–hydrology system. The efficiency of our approach, relying on localized refinement, is also demonstrated. Future work will include coupling the SUbglacial Hydrology MOdel (SUHMO) with the BISICLES AMR ice sheet model (Cornford et al., 2013), both built on the same numerical framework.

Biallelic pathogenic variants in the genes encoding the dolichol-phosphate mannose synthase subunits (DPM) which produce mannosyl donors for glycosylphosphatidylinositols, N-glycan and protein O- and C-mannosylation, are rare causes of congenital disorders of glycosylation. Pathogenic variants in DPM1 and DPM2 are associated with muscle-eye-brain (MEB) disease, whereas DPM3 variants have mostly been reported in patients with isolated muscle disease-dystroglycanopathy. Thus far, only one affected individual with compound heterozygous DPM3 variants presenting with myopathy, mild intellectual disability, seizures, and nonspecific white matter abnormalities (WMA) around the lateral ventricles has been described. Here we present five affected individuals from four unrelated families with global developmental delay/intellectual disability ranging from mild to severe, microcephaly, seizures, WMA, muscle weakness and variable cardiomyopathy. Exome sequencing of the probands revealed an ultra-rare homozygous pathogenic missense DPM3 variant NM_018973.4:c.221Agt;G, p.(Tyr74Cys) which segregated with the phenotype in all families. Haplotype analysis indicated that the variant arose independently in three families. Functional analysis did not reveal any alteration in the N-glycosylation pathway caused by the variant; however, this does not exclude its pathogenicity in the function of the DPM complex and related cellular pathways. This report provides supporting evidence that, besides DPM1 and DPM2, defects in DPM3 can also lead to a muscle and brain phenotype.

Data on depression and stress among patients with spontaneous coronary artery dissection (SCAD) are limited. Using data from the VIRGO (Variation in Recovery: Role of Gender on Outcomes of Young AMI Patients) study, which prospectively enrolled 3,572 acute myocardial infarction (AMI) patients between 18 and 55 years of age, we identified 67 SCAD cases. We compared Patient Health Questionnaire-9 (PHQ-9) and 14-item Perceived Stress Scale (PSS-14) scores obtained at baseline, 1 month, and 12 months between SCAD and AMI of all other causes. Using longitudinal linear mixed-effects analysis, we compared depression and stress scores between SCAD and other AMI, adjusting for time and selected covariates. Patients with SCAD had lower baseline PHQ-9 scores (6.1 ± 6.0 vs 7.7 ± 6.4 for other patients with AMI, p = 0.03), similar 1-month scores, and lower 12-month scores (3.2 ± 4.3 vs 4.9 ± 5.5, p = 0.004). At baseline and 1 month, patients with SCAD had similar PSS-14 scores to those of other patients with AMI. At 12 months, patients with SCAD had lower scores (18.4 ± 8.8 vs 21.5 ± 9.3 for other patients with AMI, p = 0.009). After adjustment for cardiovascular risk factors, co-morbidities, and clinical acuity, no differences in PHQ-9 or PSS-14 scores remained between SCAD and other AMI. Similar results were obtained in a subgroup analysis of only women with SCAD and other AMI. In conclusion, patients with SCAD had a relatively lower burden of depression and perceived stress than other patients with AMI, potentially because of fewer co-morbidities and favorable socioeconomic factors. However, given high depression and stress burden in both SCAD and other patients with AMI, routine screening can help identify and treat these patients.

Congenital disorders of glycosylation (CDG) and Niemann-Pick type C (NPC) disease are inborn errors of metabolism that can both present with infantile-onset severe liver disease and other multi-systemic manifestations. Plasma bile acid and N-palmitoyl-O-phosphocholineserine (PPCS) are screening biomarkers with proposed improved sensitivity and specificity for NPC. We report an infant with ATP6AP1-CDG who presented with cholestatic liver failure and elevated plasma oxysterols and bile acid, mimicking NPC clinically and biochemically. On further investigation, PPCS, but not the bile acid derivative N-(3β,5α,6β-trihydroxy-cholan-24-oyl) glycine (TCG), were elevated in plasma samples from individuals with ATP6AP1-, ALG1-, ALG8-, and PMM2-CDG. These findings highlight the importance of keeping CDG within the diagnostic differential when evaluating children with early onset severe liver disease and elevated bile acid or PPCS to prevent delayed diagnosis and treatment.

ATP6AP1-CDG is an X-linked disorder typically characterized by hepatopathy, immunodeficiency and an abnormal type II transferrin glycosylation pattern. Here, we present eleven new patients and clinical updates with biochemical characterization on one previously reported patient. We also document intrafamilial phenotypic variability and atypical presentations, expanding the symptomatology of ATP6AP1-CDG to include dystonia, hepatocellular carcinoma, and lysosomal abnormalities on hepatic histology. Three of our subjects received successful liver transplantation. We performed N-glycan profiling of total and fractionated plasma proteins for six patients and show associations with varying phenotypes, demonstrating potential diagnostic and prognostic value of fractionated N-glycan profiles. The aberrant N-linked glycosylation in purified transferrin and remaining plasma glycoprotein fractions normalized in one patient post hepatic transplant, while the increases of Man4GlcNAc2 and Man5GlcNAc2 in purified immunoglobulins persisted. Interestingly, in the single patient with isolated immune deficiency phenotype, elevated high-mannose glycans were detected on purified immunoglobulins without glycosylation abnormalities on transferrin or the remaining plasma glycoprotein fractions. Given the diverse and often tissue specific clinical presentations and the need of clinical management post hepatic transplant in ATP6AP1-CDG patients, these results demonstrate that fractionated plasma N-glycan profiling could be a valuable tool in diagnosis and disease monitoring.

Malaria cases and deaths keep being excessively high every year. Some inroads gained in the last two decades have been eroded especially due to the surge of resistance to most antimalarials. The search for new molecules that can replace the ones currently in use cannot stop. In this report, the synthesis of benzimidazole derivatives guided by structure–activity parameters is presented. Thirty-six molecules obtained are analyzed according to their activity against P. falciparum HB3 strain based on the type of substituent on rings A and B, their electron donor/withdrawing, as well as their dimension/spatial properties. There is a preference for electron donating groups on ring A, such as Me in position 5, or better, 5, 6-diMe. Ring B must be of the pyridine type such as picolinamide, other modifications are generally not favorable. Two molecules, 1 and 33 displayed antiplasmodial activity in the high nanomolar range against the chloroquine sensitive strain, with selectivity indexes above 10. Activity results of 1, 12 and 16 on a chloroquine resistance strain indicated an activity close to chloroquine for compound 1. Analysis of some of their effect on the parasites seem to suggest that 1 and 33 affect only the parasite and use a route other than interference with hemozoin biocrystallization, the route used by chloroquine and most antimalarials.

Congenital disorders of glycosylation (CDG) are ultrarare, genetically and clinically heterogeneous metabolic disorders. Although the number of identified CDG is growing rapidly, there are few therapeutic options. Most treatments involve dietary supplementation with monosaccharides or other precursors. These approaches are relatively safe, but in many cases, the molecular and biochemical underpinnings are incomplete. Recent studies demonstrate that yeast, worm, fly, and zebrafish models of CDG are powerful tools in screening repurposed drugs, ushering a new avenue to search for novel therapeutic options. Here we present a perspective on compounds that are currently in use for CDG treatment or have a potential to be applied as therapeutics in the near future.

Congenital disorders of glycosylation (CDGs) form a group of rare diseases characterized by hypoglycosylation. We here report the identification of 16 individuals from nine families who have either inherited or de novo heterozygous missense variants in STT3A, leading to an autosomal-dominant CDG. STT3A encodes the catalytic subunit of the STT3A-containing oligosaccharyltransferase (OST) complex, essential for protein N-glycosylation. Affected individuals presented with variable skeletal anomalies, short stature, macrocephaly, and dysmorphic features; half had intellectual disability. Additional features included increased muscle tone and muscle cramps. Modeling of the variants in the 3D structure of the OST complex indicated that all variants are located in the catalytic site of STT3A, suggesting a direct mechanistic link to the transfer of oligosaccharides onto nascent glycoproteins. Indeed, expression of STT3A at mRNA and steady-state protein level in fibroblasts was normal, while glycosylation was abnormal. In S. cerevisiae, expression of STT3 containing variants homologous to those in affected individuals induced defective glycosylation of carboxypeptidase Y in a wild-type yeast strain and expression of the same mutants in the STT3 hypomorphic stt3-7 yeast strain worsened the already observed glycosylation defect. These data support a dominant pathomechanism underlying the glycosylation defect. Recessive mutations in STT3A have previously been described to lead to a CDG. We present here a dominant form of STT3A-CDG that, because of the presence of abnormal transferrin glycoforms, is unusual among dominant type I CDGs. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:108 issue:11 pages:2130-2144 ispartof: location:United States status: published

Saul-Wilson syndrome is a rare skeletal dysplasia caused by a heterozygous mutation in COG4 (p.G516R). Our previous study showed that this mutation affected glycosylation of proteoglycans and disturbed chondrocyte elongation and intercalation in zebrafish embryos expressing the COG4p.G516R variant. How this mutation causes chondrocyte deficiencies remain unsolved. To analyze a disease-relevant cell type, COG4p.G516R variant was generated by CRISPR knock-in technique in the chondrosarcoma cell line SW1353 to study chondrocyte differentiation and protein secretion. COG4p.G516R cells display impaired protein trafficking and altered COG complex size, similar to SWS-derived fibroblasts. Both SW1353 and HEK293T cells carrying COG4p.G516R showed very modest, cell-type dependent changes in N-glycans. Using 3D culture methods, we found that cells carrying the COG4p.G516R variant made smaller spheroids and had increased apoptosis, indicating impaired in vitro chondrogenesis. Adding WT cells or their conditioned medium reduced cell death and increased spheroid sizes of COG4p.G516R mutant cells, suggesting a deficiency in secreted matrix components. Mass spectrometry-based secretome analysis showed selectively impaired protein secretion, including MMP13 and IGFBP7 which are involved in chondrogenesis and osteogenesis. We verified reduced expression of chondrogenic differentiation markers, MMP13 and COL10A1 and delayed response to BMP2 in COG4p.G516R mutant cells. Collectively, our results show that the Saul-Wilson syndrome COG4p.G516R variant selectively affects the secretion of multiple proteins, especially in chondrocyte-like cells which could further cause pleiotropic defects including hampering long bone growth in SWS individuals.

Biosynthesis of macromolecules requires precursors such as sugars or amino acids, originating from exogenous/dietary sources, reutilization/salvage of degraded molecules, or de novo synthesis. Since these sources are assumed to contribute to one homogenous pool, their individual contributions are often overlooked. Protein glycosylation uses monosaccharides from all the above sources to produce nucleotide sugars required to assemble hundreds of distinct glycans. Here, we demonstrate that cells identify the origin/heritage of the monosaccharide, fucose, for glycosylation. We measured the contribution of GDP-fucose from each of these sources for glycan synthesis and found that different fucosyltransferases, individual glycoproteins, and linkage-specific fucose residues identify and select different GDP-fucose pools dependent on their heritage. This supports the hypothesis that GDP-fucose exists in multiple, distinct pools, not as a single homogenous pool. The selection is tightly regulated since the overall pool size remains constant. We present novel perspectives on monosaccharide metabolism, which may have a general applicability.

Geosynthetic is a broad term given to geotextile, geomembrane, geogrid, geocell etc. It’s provenance in the 60’s was primarily the cut of construction cost and time. Ubiquitous savings were evidenced over the years. Several decades later, a new age of sustainable construction is dawning, in preserving resource, mitigating climate change and reducing greenhouse gas (GHG) emission, the best of both worlds in cost effectiveness and sustainability. But how sustainable is with the use geosynthetics. Carbon footprint assessment has been introduced to quantify any hindsight. From resin production, to manufacturing, to shipment and from site installation, to operation, to maintenance and eventually to dismantling and disposal, equivalent CO2 emission can be traced and calculated. This paper reviews some of the trends and studies on this emission benchmark development, and therefore the comparison of CO2 emission between different methods of construction with geosynthetic and that of the conventional. The picture, indeed, underpins cogent discussion. It is hoped that a change of local mind set to appreciate geosynthetic, to accept its design, to review construction rule and regulation and to educate the next generation can be way forward to underline geosynthetic as a viable sustainable construction material.

Congenital disorders of glycosylation (CDG) are a group of heterogeneous inherited metabolic disorders affecting posttranslational protein modification. DDOST-CDG, caused by biallelic pathogenic variants in DDOST which encodes dolichyl-diphospho-oligosaccharide-protein glycosyltransferase, a subunit of N-glycosylation oligosaccharyltransferase (OST) complex, is an ultra-rare condition that has been described in two patients only. The main clinical features in the two reported patients include profound developmental delay, failure to thrive, and hypotonia. In addition, both patients had abnormal transferrin glycosylation. Here, we report an 18-year-old male who presented with moderate developmental delay, progressive opsoclonus, myoclonus, ataxia, tremor, and dystonia. Biochemical studies by carbohydrate deficient transferrin analysis showed a type I CDG pattern. Exome sequencing identified compound heterozygous variants in DDOST: a maternally inherited variant, c.1142dupT (p.Leu381Phefs*11), and a paternally inherited variant, c.661 T C (p.Ser221Pro). Plasma N-glycan profiling showed mildly increased small high mannose glycans including Man

Malaria cases and deaths keep being excessively high every year. Some inroads gained in the last two decades have been eroded especially due to the surge of resistance to most antimalarials. The search for new molecules that can replace the ones currently in use cannot stop. In this report, the synthesis of benzimidazole derivatives guided by structure-activity parameters is presented. Thirty-six molecules obtained are analyzed according to their activity against P. falciparum HB3 strain based on the type of substituent on rings A and B, their electron donor/withdrawing, as well as their dimension/spatial properties. There is a preference for electron donating groups on ring A, such as Me in position 5, or better, 5, 6-diMe. Ring B must be of the pyridine type such as picolinamide, other modifications are generally not favorable. Two molecules, 1 and 33 displayed antiplasmodial activity in the high nanomolar range against the chloroquine sensitive strain, with selectivity indexes above 10. Activity results of 1, 12 and 16 on a chloroquine resistance strain indicated an activity close to chloroquine for compound 1. Analysis of some of their effect on the parasites seem to suggest that 1 and 33 affect only the parasite and use a route other than interference with hemozoin biocrystallization, the route used by chloroquine and most antimalarials.

Water flowing under ice sheets and glaciers can have a strong influence on ice dynamics, particularly through pressure changes, suggesting that a comprehensive ice sheet model should include the effect of basal hydrology. Modeling subglacial hydrology remains a challenge however, mainly due to the range of spatial and temporal scales involved - from subglacial channels to vast subglacial lakes. Additionally, networks of subglacial drainage channels dynamically evolve over time. To address some of these challenges, we have developed an Adaptive Mesh Refinement (AMR) model based on the Chombo software framework. We extend the model proposed by Sommers et al. (2018) with a few changes to accommodate the transition from unresolved to resolved flow features. We handle the strong nonlinearities present in the equations by resorting to an efficient nonlinear Full Approximation Scheme multigrid (FAS-MG) algorithm. We outline the details of the algorithm and present convergence analysis results demonstrating its effectiveness. Additionally, we present results validating our approach, using test cases from the Subglacial Hydrology Model Intercomparison Project (SHMIP) (de Fleurian et al., 2018). We finish by presenting a more complex AMR test case and discuss the effective pressure distribution as the spatial resolution increases.