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In the COVID-19 pandemic era, safety concerns have been raised regarding the risk of severe infection following administration of ocrelizumab (OCR), a B-cell-depleting therapy. We enrolled all relapsing remitting multiple sclerosis (RRMS) patients who received maintenance doses of OCR from January 2020 to June 2021. Data were extracted in December 2021. Standard interval dosing (SID) was defined as a regular maintenance interval of OCR infusion every 6 months, whereas extended interval dosing (EID) was defined as an OCR infusion delay of at least 4 weeks. Three infusions were considered in defining SID vs. EID (infusions A, B, and C). Infusion A was the last infusion before January 2020. The primary study outcome was a comparison of disease activity during the A-C interval, which was defined as either clinical (new relapses) or radiological (new lesions on T1-gadolinium or T2-weighted magnetic resonance imaging (MRI) sequences). Second, we aimed to assess confirmed disability progression (CDP). A total cohort of 278 patients (174 on SID and 104 on EID) was enrolled. Patients who received OCR on EID had a longer disease duration and a higher rate of vaccination against severe acute respiratory syndrome-coronavirus 2 (p

Lymphedema is always initially treated by combined decongestive physiotherapy (CDP). Those cases, refractory to CDP, may be managed by surgical therapy. One of the most used microsurgical procedures is represented by the technique of lymphatic-venous anastomosis (LVA). But very few papers report long term results of LVA. The aim of this study is to assess the long-term patency of multiple lymphatic-venous anastomosis (MLVA) for the treatment of secondary lymphedemas.From January 2014 to December 2014, 101 patients (mean age: 56.94 ± 8.98 years; female/male: 86/15) affected by secondary cancer-related lymphedema (38 lower and 63 upper limbs) were treated by MLVA. All lymphedemas had previously been treated by conservative therapy without sustained results. Many patients (78%) had 1-3 episodes of acute lymphangitis/year. Lymphoscintigraphy, venous duplex-ultrasonography, and abdominal or axillary ultrasound investigation were performed preoperatively. MLVA patency was assessed by the lymphatic transport index (LyTI) and lymphoscintigraphic pattern.At 1 year after surgery, excess volume reduction was 75%-90% in the early stage II secondary lymphedemas, and 60%-75% in the late stage II. The decrease in volume maintained stability in the 5-years follow-up period. Two more advanced lower and one upper limb lymphedemas had 45%-60% reduction. LyTI showed a significant decrease between the preoperative mean value (31.7 ± 9.43) and after 18 months from surgery (11.2 ± 1.91) (p .001). MLVA patency was shown in 98 (97%) patients. No patients had evidence of postoperative lymphangitis.This study demonstrated the long-term patency of MLVA in the treatment of cancer-related lymphedemas.

The environmental commitment of healthcare stakeholders is poorly described despite the sector pollution and the social needs of more sustainable behaviors. A cross-sectional study comparing the environment commitment of US publicly traded companies producing healthcare equipment (HE), healthcare companies (H), and large capitalization corporates (LC) was designed. Using a financial database, the 20 largest US publicly traded companies by market capitalization were selected for each cohort. The last available sustainability report was investigated, aiming to assess (1) the year and the method of dissemination of the last report; (2) the adhesion to environmental standards; (3) the presence of environmental policies, quantitative targets, and tracking; (4) the third-party evaluations about company environmental sustainability. HE companies published sustainability reports in time (p = 0.048), usually as standalone reports (p0.001). Half of HE companies adhered to standards, less than the control groups (p0.001). HE companies had an acceptable environmental policy, improving over the time and posing targets, similarly to control groups (p0.05). The number of companies reporting quantitative targets/tracking about carbon footprint, water, and renewable energy managements differed among the three cohorts (p = 0.013, p = 0.013, and p0.001, respectively), with HE cohort achieving the lowest rates (70%, 70%, and 50%, respectively). Carbon neutrality and all renewable energy statements were rare among HE companies (10% and 5% of companies, p0.007). In HE, CDP (The Carbon Disclosure Project) scores were lower than controls (p0.001). US publicly traded companies producing healthcare equipment demonstrated to be far less committed to environmental sustainability than healthcare companies and large capitalization corporates. Level of evidence: IV.

Background Ocrelizumab was found to decrease brain atrophy rate in primary progressive multiple sclerosis (PPMS), but no data are currently available on the effect of ocrelizumab on retinal layer thicknesses in the PPMS population. Objective To assess retinal layer changes in ocrelizumab-treated PPMS and test their possible application as biomarkers of therapy response. Methods 36 PPMS patients, treated with ocrelizumab for at least 6 months, and 39 sex- and age-matched healthy controls (HC) were included in a blind, longitudinal study. Spectrum-domain optical coherence tomography (SD-OCT) was performed at study entry (T0) and after 6 (T6) and 12 months (T12). At month 24 (T24), patients were divided into responders (no evidence of 1-year confirmed disability progression, 1y-CDP) and non-responders (evidence of 1y-CDP). Results At T24, 23/36 (64%) patients were considered responders and 13/36 (36%) non-responders. At T0, peripapillary retinal nerve fiber layer (pRNFL) thickness, macular ganglion cell–inner plexiform layer (GCIPL) and inner retinal layer (IRL) volume were significantly lower in PPMS compared to HC (p = 0.001 for all comparisons). At T6 and T12, non-responders significantly differed in the inner nuclear layer (INL) thinning rate compared to responders (p = 0.005 at both time-points). Conclusions Ocrelizumab significantly slows down INL thinning rate in PPMS responders. The longitudinal analysis of retina layer changes by means of OCT may be a promising prognostic test, and merits further investigations.

Niche theory predicts that to reduce competition for the same resource, sympatric ecologically similar species should exploit divergent niches and segregate in one or more dimensions. Seasonal variations in environmental conditions and energy requirements can influence the mechanisms and the degree of niche segregation. However, studies have overlooked the multi-dimensional aspect of niche segregation over the whole annual cycle, and key facets of species co-existence still remain ambiguous. The present study provides insights into the niche use and partitioning of two morphologically and ecologically similar seabirds, the common (CDP, Pelecanoides urinatrix) and the South Georgian diving petrel (SGDP, Pelecanoides georgicus). Using phenology, at-sea distribution, diving behavior and isotopic data (during the incubation, chick-rearing and non-breeding periods), we show that the degree of partitioning was highly stage-dependent. During the breeding season, the greater niche segregation during chick-rearing than incubation supported the hypothesis that resource partitioning increases during energetically demanding periods. During the post breeding period, while species-specific latitudinal differences were expected (species specific water mass preference), CDP and SGDP also migrated in divergent directions. This segregation in migration area may not be only a response to the selective pressure arising from competition avoidance between sympatric species, but instead, could reflect past evolutionary divergence. Such stage-dependent and context-dependent niche segregation demonstrates the importance of integrative approaches combining techniques from different fields, throughout the entire annual cycle, to better understand the co-existence of ecologically similar species. This is particularly relevant in order to fully understand the short and long-term effects of ongoing environmental changes on species distributions and communities.This work demonstrates the need of integrative multi-dimensional approaches combining concepts and techniques from different fields to understand the mechanism and causal factors of niche segregation.

Background: Siponimod significantly reduced the risk of confirmed disability progression (CDP), worsening in cognitive processing speed (CPS), relapses, and magnetic resonance imaging (MRI) measures of brain atrophy and inflammation versus placebo in secondary progressive multiple sclerosis (SPMS) patients in the Phase 3 EXPAND study. Objective: The aim of this study was to assess long-term efficacy and safety of siponimod 2 mg/day from the EXPAND study including the extension part, up to > 5 years. Methods: In the open-label extension part, participants receiving placebo during the core part were switched to siponimod (placebo-siponimod group) and those on siponimod continued the same treatment (continuous siponimod group). Results: Continuous siponimod reduced the risk of 6-month CDP by 22% (hazard ratio (HR) (95% confidence interval (CI)): 0.78 (0.66–0.92) p = 0.0026) and 6-month confirmed worsening in CPS by 23% (HR (95% CI): 0.77 (0.65–0.92) p = 0.0047) versus the placebo-siponimod group. Sustained efficacy on annualized relapse rate, total and regional brain atrophy, and inflammatory disease activity was also observed. No new, unexpected safety signals for siponimod were identified over the long term. Conclusion: The sustained efficacy and consistent long-term safety profile of siponimod up to > 5 years support its clinical utility for long-term treatment of SPMS. Benefits in the continuous siponimod versus placebo-siponimod group highlight the significance of earlier treatment initiation. Trial registration number: NCT01665144

Objective: The aim of this study is to investigate the effect of complex decongestive physiotherapy (CDP) plus intermittent pneumatic compression (IPC) applications on upper extremity circumference and volume in patients with lipedema. Methods and Results: All participants included in the study were included in a treatment protocol consisting of CDP and IPC. The Perometer 400 NT was used in the measurement of upper extremity volume and circumference before and after treatment. The measurements were performed in four reference points. According to the Perometer results before and after CDP, statistically significant reduction was found in the circumference of 3 of the 4 points of measurements performed in each of the left and right upper extremities. When the volume assessments were compared, it was seen that statistically significant reduction was found in the volume of both limbs. Conclusion: A treatment program consisting of CDP and IPC can be effective in reducing the circumference and volume of the arm in patients with upper extremity lipedema. So, CDP applications can help prevent the development of complications such as lipolymphedema, hypertension, and heart failure. Clinical Trial Registration number: NCT04643392 https://register.clinicaltrials.gov/prs/app/action/SelectProtocol?sid=S000AF9B&selectaction=Edit&uid=U00055NT&ts=2&cx=-3oevdw.

Background: Platelet-activating-factor (PAF) is a lipid inflammatory mediator implicated in liver disease. Its main biosynthetic enzymes are cytidine diphosphate (CDP)-choline: 1-alkyl-2-acetyl-sn-glycerol-cholinephosphotransferase (PAF-CPT) and acetyl-coenzyme A: lyso-PAF-acetyltransferases (Lyso-PAF-AT). At the same time, PAF acetylhydrolase (PAF-AH) and lipoprotein-associated phospholipase A2 (Lp-PLA2) degrade PAF. Objective: To explore the relation of PAF metabolism with liver diseases and non-alcoholic fatty liver disease, as reflected by the fatty liver index (FLI). Methods: In 106 healthy volunteers, PAF concentration, the activity of its metabolic enzymes and gamma-glutamyl transferase (GGT) were measured in whole blood, leukocytes and serum, respectively and the FLI was calculated. Partial correlations and linear regression models were used. Results: In males, serum GGT activity was positively correlated with abdominal fat (as assessed by analysis of a manually defined region of interest in dual-energy X-ray absorptiometry), triacylglycerols, bound-PAF and Lp-PLA2, while the FLI was positively correlated with Lp-PLA2 activity. In females, serum GGT activity was negatively associated with high-density lipoprotein cholesterol (HDL-C) (age adjusted correlations, all p2 was a significant determinant of serum GGT activity in males after controlling for age, low- density lipoprotein cholesterol (LDL-C) and abdominal fat. The addition of bound-PAF in the model significantly increased the explained variance of serum GGT activity (total variance explanation 30%). Conclusions : Bound-PAF and Lp-PLA2 activity predicted serum GGT activity while Lp-PLA2 was also related to FLI. Our findings shed light on the metabolic pathways linking Lp-PLA2 to other atherosclerosis and/or oxidative markers, such as HDL-C, LDL-C, GGT and FLI and underline the important role of PAF.

OBJECTIVE: To explore the role of 5-hydroxytryptamine (5-HT) in type 2 diabetes mellitus (T2DM)-related hepatic inflammation and fibrosis. METHODS: Male C57BL/6J mice were used to establish T2DM model by high-fat diet feeding combined with intraperitoneal injection of streptozotocin. Then, the mice with hyperglycemia were still fed with high-fat diet for nine weeks, and treated with or without 5-HT(2A) receptor (5-HT(2A)R) antagonist sarpogrelate hydrochloride (SH) and 5-HT synthesis inhibitor carbidopa (CDP) (alone or in combination). To observe the role of 5-HT in the myofibroblastization of hepa-tic stellate cells (HSCs), human HSCs LX-2 were exposed to high glucose, and were treated with or without SH, CDP or monoamine oxidase A (MAO-A) inhibitor clorgiline (CGL). Hematoxylin & eosin and Masson staining were used to detect the pathological lesions of liver tissue section, immunohistochemistry and Western blot were used to analyze protein expression, biochemical indicators were measured by ELISA or enzyme kits, and levels of intracellular reactive oxygen species (ROS) were detected by fluorescent probe. RESULTS: There were up-regulated expressions of 5-HT(2A)R, 5-HT synthases and MAO-A, and elevated levels of 5-HT in the liver of the T2DM mice. In addition to reduction of the hepatic 5-HT levels and MAO-A expression, treatment with SH and CDP could effectively ameliorate liver lesions in the T2DM mice, both of which could ameliorate hepatic injury and steatosis, significantly inhibit the increase of hepatic ROS (H(2)O(2)) levels to alleviate oxidative stress, and markedly suppress the production of transforming growth factor β1 (TGF-β1) and the development of inflammation and fibrosis in liver. More importantly, there was a synergistic effect between SH and CDP. Studies on LX-2 cells showed that high glucose could induce up-regulation of 5-HT(2A)R, 5-HT synthases and MAO-A expression, increase intracellular 5-HT level, increase the production of ROS, and lead to myofibroblastization of LX-2, resulting in the increase of TGF-β1 synthesis and production of inflammatory and fibrosis factors. The effects of high glucose could be significantly inhibited by 5-HT(2A)R antagonist SH or be markedly abolished by mitochondrial 5-HT degradation inhibitor CGL. In addition, SH significantly suppressed the up-regulation of 5-HT synthases and MAO-A induced by high glucose in LX-2. CONCLUSION: Hyperglycemia-induced myofibroblastization and TGF-β1 production of HSCs, which leads to hepatic inflammation and fibrosis in T2DM mice, is probably due to the up-regulation of 5-HT(2A)R expression and increase of 5-HT synthesis and degradation, resulting in the increase of ROS production in mitochondria. Among them, 5-HT(2A)R is involved in the regulation of 5-HT synthases and MAO-A expression.

α-Dystroglycan (α-DG) is a highly glycosylated cell-surface protein. Defective O-mannosyl glycan on α-DG is associated with muscular dystrophies and cancer. In the biosynthetic pathway of the O-mannosyl glycan, fukutin (FKTN) and fukutin-related protein (FKRP) transfer ribitol phosphate (RboP). Previously, we reported that FKTN and FKRP can also transfer glycerol phosphate (GroP) from CDP-glycerol (CDP-Gro) and showed the inhibitory effects of CDP-Gro on functional glycan synthesis by preventing glycan elongation in vitro. However, whether mammalian cells have CDP-Gro or associated synthetic machinery has not been elucidated. Therefore, the function of CDP-Gro in mammals is largely unknown. Here, we reveal that cultured human cells and mouse tissues contain CDP-Gro using liquid chromatography tandem–mass spectrometry (LC–MS/MS). By performing the enzyme activity assay of candidate recombinant proteins, we found that ethanolamine-phosphate cytidylyltransferase (PCYT2), the key enzyme in de novo phosphatidylethanolamine biosynthesis, has CDP-Gro synthetic activity from glycerol-3-phosphate (Gro3P) and CTP. In addition, knockdown of PCYT2 dramatically reduced cellular CDP-Gro. These results indicate that PCYT2 is a CDP-Gro synthase in mammals. Furthermore, we found that the expression of functionally glycosylated α-DG is increased by reducing PCYT2 expression. Our results suggest an important role for CDP-Gro in the regulation of α-DG function in mammals.

Autophagy, a conserved eukaryotic intracellular catabolic pathway, maintains cell homeostasis by lysosomal degradation of cytosolic material engulfed in double membrane vesicles termed autophagosomes, which form upon sealing of single-membrane cisternae called phagophores. While the role of phosphatidylinositol 3-phosphate (PI3P) and phosphatidylethanolamine (PE) in autophagosome biogenesis is well-studied, the roles of other phospholipids in autophagy remain rather obscure. Here we utilized budding yeast to study the contribution of phosphatidylcholine (PC) to autophagy. We reveal for the first time that genetic loss of PC biosynthesis via the CDP-DAG pathway leads to changes in lipid composition of autophagic membranes, specifically replacement of PC by phosphatidylserine (PS). This impairs closure of the autophagic membrane and autophagic flux. Consequently, we show that choline-dependent recovery of de novo PC biosynthesis via the CDP-choline pathway restores autophagosome formation and autophagic flux in PC-deficient cells. Our findings therefore implicate phospholipid metabolism in autophagosome biogenesis.

The disease-producing capacity of the opportunistic pathogen Enterococcus faecalis is enhanced by the ability of the bacterium to evade killing by antimicrobial agents. Survival of E. faecalis in the presence of the human antimicrobial enzyme lysozyme is mediated in part by the site 2 metalloprotease Eep; however, a complete model of enterococcal lysozyme resistance has not been elucidated. To better understand the molecular basis for lysozyme resistance in E. faecalis, we analyzed Δeep suppressor mutants that acquire resistance to lysozyme through mutation of the gene OG1RF_11713, a predicted teichoic acid biosynthesis-encoding gene located within the variable region of the enterococcal polysaccharide antigen (epa) locus. Sequence comparisons revealed that OG1RF_11713 is most similar to the cytidine-5′-diphosphate (CDP)-glycerol:poly-(glycerolphosphate)glycerophosphotransferase TagF from Staphylococcus epidermidis. Inactivation of OG1RF_11713 in both the wild-type and Δeep genetic backgrounds was sufficient to increase the resistance of E. faecalis OG1RF to lysozyme. Minimal amounts of N-acetylgalactosamine were detectable in cell wall carbohydrate extracts of OG1RF_11713 deletion mutants, and this was associated with a reduction in negative cell surface charge. Targeted disruption of OG1RF_11713 was also associated with increased susceptibility to the antibiotic polymyxin B and membrane-targeting detergents and decreased susceptibility to the lantibiotic nisin. This work implicates OG1RF_11713 as a major determinant of cell envelope integrity and provides further validation that lysozyme resistance is intrinsically linked to the modification of enterococcal cell wall polysaccharides. IMPORTANCE Enterococcus faecalis is a leading cause of health-care-associated infections for which there are limited treatment options. E. faecalis is resistant to several antibiotics and to high concentrations of the human antimicrobial enzyme lysozyme. The molecular mechanisms that mediate lysozyme resistance in E. faecalis are complex and remain incompletely characterized. This work demonstrates that a gene located within the variable region of the enterococcal polysaccharide antigen locus of E. faecalis strain OG1RF (OG1RF_11713), which is predicted to encode a component of the teichoic acid biosynthesis machinery, is part of the lysozyme resistance circuitry and is important for enterococcal cell wall integrity. These findings suggest that OG1RF_11713 is a potential target for new therapeutic strategies to combat enterococcal infections.

Cystine-dense peptides (CDPs) are a miniprotein class that can drug difficult targets with high affinity and low immunogenicity. Tools for their design, however, are not as developed as those for small-molecule and antibody drugs. CDPs have diverse taxonomic origins, but structural characterization is lacking. Here, we adapted Iterative Threading ASSEmbly Refinement (I-TASSER) and Rosetta protein modeling software for structural prediction of 4298 CDP scaffolds and performed in silico prescreening for CDP binders to targets of interest. Mammalian display screening of a library of docking-enriched, methionine and tyrosine scanned (DEMYS) CDPs against PD-L1 yielded binders from four distinct CDP scaffolds. One was affinity-matured, and cocrystallography yielded a high-affinity ( K D = 202 pM) PD-L1–binding CDP that competes with PD-1 for PD-L1 binding. Its subsequent incorporation into a CD3-binding bispecific T cell engager produced a molecule with pM-range in vitro T cell killing potency and which substantially extends survival in two different xenograft tumor-bearing mouse models. Both in vitro and in vivo, the CDP-incorporating bispecific molecule outperformed a comparator antibody-based molecule. This CDP modeling and DEMYS technique can accelerate CDP therapeutic development.

In this work, β-cyclodextrin porous polymers (P-CDPs) functionalized novel covalent organic frameworks (P-CDPs/COFs) were synthesized by a simple and facile method. After combined with Pd

Fungal spoilage led to a considerable economic loss of foodstuff which ultimately affects public health due to mycotoxins production. Moreover, the consumption of commercial antifungal drugs creates side effects and develops antifungal resistance. To overcome these challenges, the current work was aimed to investigate novel antifungal cyclic dipeptide (CDP) from Lactobacillus coryniformis (Loigolactobacillus coryniformis) BCH-4. CDPs have flexible, cyclic, and stable conformation. The proline-based CDPs provide additional structural compatibility and bio-functional values. Keeping in view, high-performance liquid chromatography (HPLC) was performed to explore cyclo(L-Leu-L-Pro) from L. coryniformis BCH-4. The HPLC detected concentration (135 ± 7.07 mg/mL) exhibited in vitro antifungal activity of 5.66 ± 0.57 mm (inhibitory zone) against Aspergillus flavus. Based on these results, cyclo(L-Leu-L-Pro) was used as a bioprotectant for selected food samples (grapes, lemon, cashew nuts, and almonds). A significant impact of cyclo(L-Leu-L-Pro) was observed in contrast with MRS broth (control) and cell-free supernatant. In silico molecular docking analysis of this CDP was carried out against FAD glucose dehydrogenase, dihydrofolate reductase, and urate oxidase of A. flavus as target proteins. Among these proteins, FAD glucose dehydrogenase exerted strong interactions with cyclo(L-Leu-L-Pro) having S-score of - 8.21. The results evaluated that the detected CDP has strong interactions with selected proteins, causing excellent growth inhibition of A. flavus. Therefore, cyclo(L-Leu-L-Pro) could be used as a potent bioprotectant against food-borne pathogenic fungi.

Background Soluble cello-oligosaccharides (COS, β‐1,4‐D‐gluco‐oligosaccharides with degree of polymerization DP 2–6) have been receiving increased attention in different industrial sectors, from food and feed to cosmetics. Development of large-scale COS applications requires cost-effective technologies for their production. Cascade biocatalysis by the three enzymes sucrose-, cellobiose- and cellodextrin phosphorylase is promising because it enables bottom-up synthesis of COS from expedient substrates such as sucrose and glucose. A whole-cell-derived catalyst that incorporates the required enzyme activities from suitable co-expression would represent an important step towards making the cascade reaction fit for production. Multi-enzyme co-expression to reach distinct activity ratios is challenging in general, but it requires special emphasis for the synthesis of COS. Only a finely tuned balance between formation and elongation of the oligosaccharide precursor cellobiose results in the desired COS. Results Here, we show the integration of cellodextrin phosphorylase into a cellobiose-producing whole-cell catalyst. We arranged the co-expression cassettes such that their expression levels were upregulated. The most effective strategy involved a custom vector design that placed the coding sequences for cellobiose phosphorylase (CbP), cellodextrin phosphorylase (CdP) and sucrose phosphorylase (ScP) in a tricistron in the given order. The expression of the tricistron was controlled by the strong T7lacO promoter and strong ribosome binding sites (RBS) for each open reading frame. The resulting whole-cell catalyst achieved a recombinant protein yield of 46% of total intracellular protein in an optimal ScP:CbP:CdP activity ratio of 10:2.9:0.6, yielding an overall activity of 315 U/g dry cell mass. We demonstrated that bioconversion catalyzed by a semi-permeabilized whole-cell catalyst achieved an industrial relevant COS product titer of 125 g/L and a space–time yield of 20 g/L/h. With CbP as the cellobiose providing enzyme, flux into higher oligosaccharides (DP ≥ 6) was prevented and no insoluble products were formed after 6 h of conversion. Conclusions A whole-cell catalyst for COS biosynthesis was developed. The coordinated co-expression of the three biosynthesis enzymes balanced the activities of the individual enzymes such that COS production was maximized. With the flux control set to minimize the share of insolubles in the product, the whole-cell synthesis shows a performance with respect to yield, productivity, product concentration and quality that is promising for industrial production.

Trypanosomiasis is a major illness affecting camels in tropical and subtropical regions. Comparisons of camel and Trypanosoma evansi genomes can lead to the discovery of new drug targets for treating Trypanosoma infections. The synthesis pathways of cytosine, cytidine, cytidine monophosphate (CMP), cytidine diphosphate (CDP), cytidine triphosphate (CTP) deoxycytidine, deoxycytidine monophosphate (dCMP), deoxycytidine diphosphate (dCDP), and deoxycytidine triphosphate (dCTP) were compared in the dromedary camel (Camelus dromedarius) and T. evansi. None of the enzymes involved in cytosine pathway were detected in camels and T. evansi. Notably, cytidine kinase (CK) and 5′-nucleotidase, which interconverts cytidine to CMP, were not detected in T. evansi but were present in camels. UMP/CMP kinase was not predicted in T. evansi. Therefore, the presence of enzymes involved in the CTP synthesis cascade was not predicted in T. evansi. CMP synthesis might also be encoded by other enzymes, e.g., purine nucleotides kinases. Both camel and T. evansi share an efficient enzyme system for converting CDP to CTP. In conclusion, CTP synthase is important for homeostasis of cytosine nucleotides in T. evansi and could be a potential drug target against the parasite. In addition, the inhibition of UMP synthesis might contribute to parasite death as it is a shared source for CTP synthesis.

Dystroglycanopathy, a subgroup of muscular dystrophies, is characterized by hypoglycosylation of α-dystroglycan (α-DG), which reduces its laminin-binding activity to extracellular matrix proteins, causing progressive loss of muscle integrity and function. Mutations in the fukutin-related protein (FKRP) gene are the most common causes of dystroglycanopathy. FKRP transfers ribitol-5-phosphate to the O-mannosyl glycan on α-DG from substrate cytidine diphosphate (CDP)-ribitol, which is synthesized by isoprenoid synthase domain-containing protein (ISPD). We previously reported that oral administration of ribitol restores therapeutic levels of functional glycosylation of α-DG (F-α-DG) in a FKRP mutant mouse model. Here we examine the contribution of adeno-associated virus (AAV)-mediated overexpression of ISPD to the levels of CDP-ribitol and F-α-DG with and without ribitol supplementation in the disease model. ISPD overexpression alone and in combination with ribitol improves dystrophic phenotype. Furthermore, the combined approach of ribitol and ISPD acts synergistically, increasing F-α-DG up to 40% of normal levels in cardiac muscle and more than 20% in limb and diaphragm. The results suggest that low levels of substrate limit production of CDP-ribitol, and endogenous ISPD also becomes a limiting factor in the presence of a supraphysiological concentration of ribitol. Our data support further investigation of the regulatory pathway for enhancing efficacy of ribitol supplement to FKRP-related dystroglycanopathy.

Human O-phosphoethanolamine phospho-lyase (hEtnppl; EC 4.2.3.2) is a pyridoxal 5′-phosphate-dependent enzyme that catalyzes the degradation of O-phosphoethanolamine (PEA) into acetaldehyde, phosphate and ammonia. Physiologically, the enzyme is involved in phospholipid metabolism, as PEA is the precursor of phosphatidylethanolamine in the CDP-ethanolamine (Kennedy) pathway. Here, the crystal structure of hEtnppl in complex with pyridoxamine 5′-phosphate was determined at 2.05 Å resolution by molecular replacement using the structure of A1RDF1 from Arthrobacter aurescens TC1 (PDB entry 5g4i) as the search model. Structural analysis reveals that the two proteins share the same general fold and a similar arrangement of active-site residues. These results provide novel and useful information for the complete characterization of the human enzyme.

Supernova is a chemiluminescent deoxyribozyme recently discovered in our group. It transfers the phosphate group from the 1,2-dioxetane substrate CDP-Star to its 5' hydroxyl group, which triggers a decomposition reaction and the production of light. Here we investigated the effects of reaction conditions on the ability of Supernova to generate a chemiluminescent signal (using a plate reader assay) and to phosphorylate itself (using a ligation assay). Our experiments indicate that multiple zinc ions are required for catalytic function, suggesting links between Supernova and protein enzymes that catalyze similar reactions. They also show how factors such as pH, potassium concentration, CDP-Star concentration, and DNA concentration affect the reaction. By combining information from different experiments, the rate enhancement of light production was increased by more than 1000-fold. These results should be useful for applications in which Supernova is used as a sensor.

Essential tremor (ET) is a neurological disorder characterized primarily by action tremor. Balance impairments in ET patients were formerly considered to be uncommon and simply age-related. However quantitative assessment with posturography has revealed impairments in control of both static and dynamic balance.The aim of the present study is to assess postural stability with different posturographic techniques in ET patients.A prospective cross-sectional study conducted in two University Hospitals. Eleven patients diagnosed with essential tremor and twelve healthy controls were included. Balance assessment were performed with: sensory organization test (SOT) and limits of stability (LOS) of the computer dynamic posturography (CDP), results of free-field body sway analysis with mobile posturography (Vertiguard®), modified timed up and go test (TUG), Dizziness handicap inventory (DHI) and activities-specific balance confidence scale (ABC).Patients with ET showed poorer scores in the SOT than controls for composite balance and somatosensory input. They also performed worse in LOS tests and Vertiguard® device indicated a higher risk of falling. There were no differences in the modified TUG. The mean score of DHI was 15.64 and 85.16 for ABC.Posturography assessment (CDP and Vertiguard®) is more accurate in showing balance impairment in ET patients than clinical evaluation (modified TUG). Balance impairment involves deteriorated processing of somatosensory input which could be explained by cerebellar dysfunction. Balance deficits could be included into future diagnostic criteria.

Background and objectives. Edentulism is a major public health concern globally relating to extensive loss of teeth. Due to paucity of study, this research aimed to explore the perception of edentulous patients (EDPs) and dental professionals (DPs) towards care and maintenance given to complete denture prostheses (CDP) in Fiji. Methods. A descriptive qualitative study was conducted among 30 EDPs attending dental prosthetic clinics (DPCs) at the four centres in Fiji and 28 DPs at the four DPCs under purposive sampling. Semi-structured questionnaire with open-ended questions was used for in-depth interview (IDI) with EDPs via telephone and focus group discussion (FGD) with DPs virtually via Zoom. Participant responses were recorded and thematic analysis was used to manually analyze the verbatim transcripts. Results. Five themes were identified as perceptions of EDPs towards care and maintenance of CDP in Fiji: patient perceptions towards CDP, CDP care and maintenance, communication between DPs and EDPs, challenges faced in CDP, and management strategies to CDP care and maintenance. Seven themes were identified as perceptions of DPs: CDP guidelines, post-denture insertion advice, care and maintenance, challenges while treating EDPs, management strategies to challenges faced, communication and teamwork, and recommendations to improving quality of CDP delivery in Fiji. Conclusion. Patients’ perception towards care and maintenance of CDP was low. It is highly recommended for EDPs to adhere to CDP advice given by DPs whilst for DPs, it had been recommended to provide written, oral, and visual forms of CDP care and maintenance advice to EDPs for effectiveness.

Ribitol-phosphate modification is crucial for the functional maturation of α-dystroglycan. Its dysfunction is associated with muscular dystrophy, cardiomyopathy, and central nervous system abnormalities; however, no effective treatments are currently available for diseases caused by ribitol-phosphate defects. In this study, we demonstrate that prodrug treatments can ameliorate muscular dystrophy caused by defects in isoprenoid synthase domain containing (ISPD), which encodes an enzyme that synthesizes CDP-ribitol, a donor substrate for ribitol-phosphate modification. We generated skeletal muscle-selective Ispd conditional knockout mice, leading to a pathogenic reduction in CDP-ribitol levels, abnormal glycosylation of α-dystroglycan, and severe muscular dystrophy. Adeno-associated virus-mediated gene replacement experiments suggested that the recovery of CDP-ribitol levels rescues the ISPD-deficient pathology. As a prodrug treatment strategy, we developed a series of membrane-permeable CDP-ribitol derivatives, among which tetraacetylated CDP-ribitol ameliorated the dystrophic pathology. In addition, the prodrug successfully rescued abnormal α-dystroglycan glycosylation in patient fibroblasts. Consequently, our findings provide proof-of-concept for supplementation therapy with CDP-ribitol and could accelerate the development of therapeutic agents for muscular dystrophy and other diseases caused by glycosylation defects.

Taihu Lake is the most important drinking water source of the major cities in the Yangtze River Delta. The pollution of endocrine disruptors (EDCs)in Taihu Lake has been increasing recently, the accurate determination is an important guide for predicting its health risks and developing appropriate controls. Monitoring organic pollutants in water using the diffusive gradient in thin film technique (DGT) has attracted much attention due to more accuracy and convenience than the grab sampling methods. In this study, a novel cyclodextrin polymer (CDP) synthesized by the simple and green method in water was taken as an adsorbent for the binding gel. Four endocrine-disrupting chemicals (EDCs), bisphenol A (BPA), 17α-ethinylestradiol (EE2), 17β-estradiol (E2), and estriol (E3), were taken as models to determine the diffusion coefficients (4.68 × 10

Although plasma, especially atmospheric plasma generated by corona discharge, has been proven to be effective in sterilization and food preservation, its disinfection mechanism on chilled pork is poorly understood. In this research, the bactericidal and preservation effect of corona discharge plasma (CDP) was investigated. The maximum bactericidal effect was found after 20 kV 4 kHz CDP treatment, with 2.77 log (colony-forming unit [CFU]/g), 2.41 log (CFU/g), and 1.36 log (CFU/g) reduction for

Translocator assembly and maintenance 41 (Tam41) catalyses the synthesis of cytidine diphosphate diacylglycerol (CDP-DAG), which is a high-energy intermediate phospholipid critical for generating cardiolipin in mitochondria. Although Tam41 is present almost exclusively in eukaryotic cells, a Firmicutes bacterium contains the gene encoding Tam41-type CDP-DAG synthase (FbTam41). FbTam41 converted phosphatidic acid (PA) to CDP-DAG using a ternary complex mechanism in vitro. Additionally, FbTam41 functionally substituted yeast Tam41 in vivo. These results demonstrate that Tam41-type CDP-DAG synthase functions in some prokaryotic cells. We determined the crystal structure of FbTam41 lacking the C-terminal 18 residues in the cytidine triphosphate (CTP)-Mg2+ bound form at a resolution of 2.6 Å. The crystal structure showed that FbTam41 contained a positively charged pocket that specifically accommodated CTP-Mg2+ and PA in close proximity. By using this structure, we constructed a model for the full-length structure of FbTam41 containing the last a-helix, which was missing in the crystal structure. Based on this model, we propose a molecular mechanism for CDP-DAG synthesis in bacterial cells and mitochondria.

Phospholipids are the major components of the membrane in all type of cells and organelles. They also are critical for cell metabolism, signal transduction, the immune system and other critical cell functions. The biosynthesis of phospholipids is a complex multi-step process with high-energy intermediates. Several enzymes in different metabolic pathways are involved in the initial phospholipid synthesis and its subsequent conversion. While the “Kennedy pathway” is the main pathway in mammalian cells, in bacteria and lower eukaryotes the precursor CDP-DAG is used in the de novo pathway by CDP-DAG alcohol O-phosphatidyl transferases to synthetize the basic lipids. Here we present the high-resolution structures of phosphatidyl serine synthase from Methanocaldococcus jannaschii crystallized in four different states. Detailed structural and functional analysis of the different structures allowed us to identify the substrate binding site and show how CDP-DAG, serine and two essential metal ions are bound and oriented relative to each other. In close proximity to the substrate binding site, two anions were identified that appear to be highly important for the reaction. The structural findings were confirmed by functional activity assays and suggest a model for the catalytic mechanism of CDP-DAG alcohol O-phosphatidyl transferases, which synthetize the phospholipids essential for the cells., CDP-diacylglycerol (CDP-DAG) alcohol O-phosphatidyl transferases (CDP-APs) are conserved in archaea, bacteria, and eukaryotes and catalyze the de novo synthesis of phospho-lipids from the precursor CDP-DAG and an alcohol. Here, the authors present the crystal structures of the Methanocaldococcus jannaschii phosphatidyl serine synthase (MjPSS) in four different states and suggest a model for its catalytic mechanism.

New/enlarging T2 lesion count and T2-lesion volume (LV) are used as conventional secondary endpoints in clinical trials of patients with multiple sclerosis (PwMS). However, those outcomes may have several limitations, such as inability to account for heterogeneity of lesion formation/enlargement frequency and their dynamic volumetric behavior. Measurement of volume rather than count of new/enlarging lesions may be more representative outcome of dynamic changes over time.To investigate whether new/enlarging T2-LV is more predictive of confirmed disability progression (CDP), compared to total T2-LV or new/enlarging T2 lesion count over long-term follow-up.We studied 176 early relapsing-remitting PwMS who were followed with annual MRI examinations over 10 years. T2-LV, new/enlarging T2-LV, and new/enlarging lesion count were determined. Cumulative count/volumes were obtained. 10-year CDP was confirmed after 48-weeks. ANCOVA analysis detected MRI outcome differences in stable (n = 76) and CDP (n = 100) groups at different time points, after correction for multiple comparisons.PwMS with CDP had greater cumulative new/enlarging T2-LV at 4 years (p = 0.049), and enlarging T2-LV at 4- (p = 0.039) and 6-year follow-up (p = 0.032), compared to stable patients. PwMS with CDP did not differ from stable ones in new/enlarging T2 lesion count or total T2-LV at any of the study timepoints. PwMS with Expanded Disability Status Scale change2.0 had significantly greater enlarging T2 lesion count (p = 0.01) and enlarging T2-LV (p = 0.038) over the 10-year follow-up.Enlargement of T2 lesions is more strongly associated with long-term disability progression compared to other conventional T2 lesion-based outcomes.

Ofatumumab is a subcutaneously administered anti-CD20 monoclonal antibody (MoAb) therapy that has been evaluated in two identically designed randomized controlled trials (RCTs), ASCLEPIOS I (NCT02792218) and ASCLEPIOS II (NCT02792231), in patients with relapsing multiple sclerosis (RMS). Ocrelizumab is another anti-CD20 MoAb therapy, administered intravenously, that has been evaluated in two identically designed RCTs, OPERA I (NCT01247324) and OPERA II (NCT01412333) in RMS. Given the absence of published RCTs with head-to-head comparisons between these MoAbs, this study assessed the indirect comparative efficacy of ofatumumab and ocrelizumab.Given the availability of individual patient data for ASCLEPIOS I/II and summary-level data for OPERA I/II, simulated treatment comparisons were used to assess the comparative efficacy of ofatumumab versus ocrelizumab while adjusting for differences in baseline characteristics between trials. Comparative efficacy was estimated for the proportion of patients with 3- and 6-month confirmed disability progression (CDP) and for annualized relapse rate (ARR). Exploratory analyses were conducted for the outcome of no evidence of disease activity based on three parameters (NEDA-3) and magnetic resonance imaging (MRI) outcomes (proportion of patients with gadolinium-enhancing T1 lesions and brain volume change).Although comparative results were not significant for 3-month CDP (hazard ratio [HR]: 0.90 [95% confidence interval [CI]: 0.57-1.42]) or 6-month CDP (HR: 0.84 [95% CI: 0.47-1.49]), ofatumumab showed a significant improvement in ARR (rate ratio: 0.60 [95% CI: 0.43-0.84]) compared with ocrelizumab. Significantly favorable results were also associated with ofatumumab for NEDA-3 and MRI outcomes.Ofatumumab was associated with more favorable efficacy results compared with ocrelizumab for clinical, NEDA-3, and MRI outcomes.

Selenoprotein I (selenoi) is a unique selenocysteine (Sec)-containing protein widely expressed throughout the body. Selenoi belongs to two different protein families: the selenoproteins that are characterized by a redox reactive Sec residue and the lipid phosphotransferases that contain the highly conserved cytidine diphosphate (CDP)-alcohol phosphotransferase motif. Selenoi catalyzes the third reaction of the CDP-ethanolamine branch of the Kennedy pathway within the endoplasmic reticulum membrane. This is not a redox reaction and does not directly involve the Sec residue, making selenoi quite distinct among selenoproteins. Selenoi is also unique among lipid phosphotransferases as the only family member containing a Sec residue near its C-terminus that serves an unknown function. The reaction catalyzed by selenoi involves the transfer of the ethanolamine phosphate group from CDP-ethanolamine to one of two lipid donors, 1,2-diacylglycerol (DAG) or 1-alkyl-2-acylglycerol (AAG), to produce PE or plasmanyl PE, respectively. Plasmanyl PE is subsequently converted to plasmenyl PE by plasmanylethanolamine desaturase. Both PE and plasmenyl PE are critical phospholipids in the central nervous system (CNS), as demonstrated through clinical studies involving SELENOI mutations as well as studies in cell lines and mice. Deletion of SELENOI in mice is embryonic lethal, while loss-of-function mutations in the human SELENOI gene have been found in rare cases leading to a form of hereditary spastic paraplegia (HSP). HSP is an upper motor disease characterized by spasticity of the lower limbs, which is often manifested with other symptoms such as impaired vision/hearing, ataxia, cognitive/intellectual impairment, and seizures. This article will summarize the current understanding of selenoi as a metabolic enzyme and discuss its role in the CNS physiology and pathophysiology.

BACKGROUND Trypanosoma cruzi crosses the placental barrier and produces the congenital transmission of Chagas disease (CD). Structural alterations of the chorionic villi by this parasite have been described in vitro, but little is known about trophoblast turnover in placentas from women with CD. OBJECTIVE To analyze the proliferation and fusion processes in placentas from women with CD. METHODS Archived human term placenta paraffin-embedded blocks were used, from women with CD (CDP), and no pathology (NP). Immunohistochemistry tests were performed for Ki67 to calculate the proliferation index (PI) of cytotrophoblast (CTB) and Syncytin-1, a fusion marker of syncytiotrophoblast (STB). Hematoxylin/Eosin stained sections were employed to analyze STB percentages, STB detachment areas and syncytial knots quantity. Non parametric Student’s t-tests were performed (p < 0.05). RESULTS Syncytial knots and STB detachment significantly increased in placental villi from the CDP group. STB percentage was significantly lower in the CDP group as well as the PI and Syncytin-1 expression significantly decreased in these placentas, compared with control (NP). CONCLUSION Dynamic of trophoblast turnover is altered in placentas from women with CD. These changes may lead into a gap in the placental barrier possibly allowing the parasite entry into the chorionic villi.

Background: Interventions targeting the adaptive immune response are needed in multiple sclerosis (MS). Objective: Evaluate laquinimod’s efficacy, safety, and tolerability in patients with relapsing-remitting multiple sclerosis (RRMS). Methods: CONCERTO was a randomized, double-blind, placebo-controlled, phase-3 study. RRMS patients were randomized 1:1:1 to receive once-daily oral laquinimod 0.6 or 1.2 mg or placebo for ⩽24 months ( n = 727, n = 732, and n = 740, respectively). Primary endpoint was time to 3-month confirmed disability progression (CDP). The laquinimod 1.2-mg dose arm was discontinued (1 January 2016) due to cardiovascular events at high doses. Safety was monitored throughout the study. Results: CONCERTO did not meet the primary endpoint of significant effect with laquinimod 0.6-mg versus placebo on 3-month CDP (hazard ratio: 0.94; 95% confidence interval: 0.67–1.31; p = 0.706). Secondary endpoint p values were nominal and non-inferential. Laquinimod 0.6 mg demonstrated 40% reduction in percent brain volume change from baseline to Month 15 versus placebo ( p Conclusion: Laquinimod 0.6 mg demonstrated only nominally significant effects on clinical relapses and magnetic resonance imaging (MRI) outcomes and was generally well tolerated. Clinical trial registration number: ClinicalTrials.gov (NCT01707992).

Technique Description with clinical presentation Correlates.Revisit and discuss the advantages of the cervicodeltopectoral flap (CDP) as an alternative to microvascular reconstruction for head and neck cutaneous defects.Retrospective chart review was performed on 2 patients with prior large cutaneous facial defects after tumor resection followed by cervicodeltopectoral flap reconstruction. These cases were performed at a single institution. The tumor resections, flap reconstructions, and postoperative management were led by the listed senior author (SPK).A 78-year-old (Clinical presentation 1) and 62-year-old (Clinical presentation 2) were evaluated for large nonmelanoma skin cancers of the face. Due to significant comorbidities, neither patient was an ideal candidate for microsurgical reconstruction. In both cases, lesion resection and CDP flap reconstruction was performed. The reconstruction allowed for successful coverage without significant donor site morbidity for each patient.The authors propose the addition of the CDP flap to the armamentarium of the head and neck reconstructive surgeon as a safe and reliable alternative to microvascular reconstruction.

Vaz, McDermott et al. identify variants in PCYT2, which encodes a key gene in phospholipid biosynthesis, in five individuals with a new complex hereditary spastic paraplegia. Functional studies in fibroblasts and a zebrafish model confirm the pathogenic nature of the variants, while lipidomic analysis reveals potential treatment strategies and plasma biomarkers., CTP:phosphoethanolamine cytidylyltransferase (ET), encoded by PCYT2, is the rate-limiting enzyme for phosphatidylethanolamine synthesis via the CDP-ethanolamine pathway. Phosphatidylethanolamine is one of the most abundant membrane lipids and is particularly enriched in the brain. We identified five individuals with biallelic PCYT2 variants clinically characterized by global developmental delay with regression, spastic para- or tetraparesis, epilepsy and progressive cerebral and cerebellar atrophy. Using patient fibroblasts we demonstrated that these variants are hypomorphic, result in altered but residual ET protein levels and concomitant reduced enzyme activity without affecting mRNA levels. The significantly better survival of hypomorphic CRISPR-Cas9 generated pcyt2 zebrafish knockout compared to a complete knockout, in conjunction with previously described data on the Pcyt2 mouse model, indicates that complete loss of ET function may be incompatible with life in vertebrates. Lipidomic analysis revealed profound lipid abnormalities in patient fibroblasts impacting both neutral etherlipid and etherphospholipid metabolism. Plasma lipidomics studies also identified changes in etherlipids that have the potential to be used as biomarkers for ET deficiency. In conclusion, our data establish PCYT2 as a disease gene for a new complex hereditary spastic paraplegia and confirm that etherlipid homeostasis is important for the development and function of the brain.

Phospholipids and phytic acid are important phosphorus (P)-containing compounds in rice grains. Phytic acid is considered as a major antinutrient, because the negatively charged phytic acid chelates cations, including essential micronutrients, and decreases their bioavailability to human beings and monogastric animals. To gain an insight into the interplay of these two kinds of phosphorus-containing metabolites, we used the CRISPR/Cas9 system to generate mutants of a phospholipase D gene (OsPLDα1) and analyzed the mutational effect on metabolites, including phytic acid in rice grains. Metabolic profiling of two ospldα1 mutants revealed depletion in the phosphatidic acid production and lower accumulation of cytidine diphosphate diacylglycerol and phosphatidylinositol. The mutants also showed significantly reduced phytic acid content as compared to their wild-type parent, and the expression of the key genes involved in the phytic acid biosynthesis was altered in the mutants. These results demonstrate that OsPLDα1 not only plays an important role in phospholipid metabolism but also is involved in phytic acid biosynthesis, most probably through the lipid-dependent pathway, and thus revealed a potential new route to regulate phytic acid biosynthesis in rice.

CMP-N-acetylneuraminate synthetase (CMAS) is a key enzyme in the sialic acid incorporation pathway and plays a crucial role in the virulence and survival of several pathogenic bacteria. Here, the structural and functional properties of CMAS from the pathogenic bacterium Vibrio cholerae are reported. Upon CDP binding, a partial domain closure is observed that was previously unreported in homologous structures. Kinetic studies reveal that the enzyme shows substrate promiscuity and can activate both Neu5Ac and Neu5Gc., Several pathogenic bacteria utilize sialic acid, including host-derived N-acetylneuraminic acid (Neu5Ac), in at least two ways: they use it as a nutrient source and as a host-evasion strategy by coating themselves with Neu5Ac. Given the significant role of sialic acid in pathogenesis and host-gut colonization by various pathogenic bacteria, including Neisseria meningitidis, Haemophilus influenzae, Pasteurella multocida and Vibrio cholerae, several enzymes of the sialic acid catabolic, biosynthetic and incorporation pathways are considered to be potential drug targets. In this work, findings on the structural and functional characterization of CMP-N-acetylneuraminate synthetase (CMAS), a key enzyme in the incorporation pathway, from Vibrio cholerae are reported. CMAS catalyzes the synthesis of CMP-sialic acid by utilizing CTP and sialic acid. Crystal structures of the apo and the CDP-bound forms of the enzyme were determined, which allowed the identification of the metal cofactor Mg2+ in the active site interacting with CDP and the invariant Asp215 residue. While open and closed structural forms of the enzyme from eukaryotic and other bacterial species have already been characterized, a partially closed structure of V. cholerae CMAS (VcCMAS) observed upon CDP binding, representing an intermediate state, is reported here. The kinetic data suggest that VcCMAS is capable of activating the two most common sialic acid derivatives, Neu5Ac and Neu5Gc. Amino-acid sequence and structural comparison of the active site of VcCMAS with those of eukaryotic and other bacterial counterparts reveal a diverse hydrophobic pocket that interacts with the C5 substituents of sialic acid. Analyses of the thermodynamic signatures obtained from the binding of the nucleotide (CTP) and the product (CMP-sialic acid) to VcCMAS provide fundamental information on the energetics of the binding process.

Objective Vestibular Migraine (VM) is the second most common cause in patients with vertigo. Patients with VM complain about vestibular symptoms during a headache attack or during the period between attacks. Vestibular Rehabilitation (VR), an exercised based therapy to treat dizziness and balance dysfunction has been shown to be effective in vestibular diseases. In this study, we aimed to assess the effect of VR for vestibular symptoms and quality of life in VM patients, and to compare the results with patients with vestibular disorders without migraine. Methods Sixty (60) patients who received VR treatment were divided into two groups: vestibular migraine group (30 patients) and non-migraine vestibular dysfunction group (30 patients). All patients received VR for 18 sessions and the program was completed in 1.5 months. Pre- and post-treatment Dizziness Handicap Inventory (DHI) scores, Vestibular Disorders Activities of Daily Living Scale (VADL) scores, the frequency of dizziness and headache, and Computerized Dynamic Posturography (CDP) scores were assessed and compared retrospectively. Results With VR in both the vestibular migraine group and vestibular dysfunction group, DHI score, VADL score, the frequency of dizziness and headache scores significantly impaired. Post-treatment CDP results were higher than pre- treatment results for both patient groups. Conclusion With VR, a significant improvement was observed in subjective and objective balance assessment measurement. Vestibular Rehabilitation must be considered in patients who do not benefit from medical therapy or have limited benefit. Level of evidence Level III (evidence obtained from well-designed controlled trials without randomization).

Polysialic acids are bioactive carbohydrates found in eukaryotes and some bacterial pathogens. The bacterial polysialyltransferases (PSTs), which catalyze the synthesis of polysialic acid capsules, have previously been identified in select strains of Escherichia coli and Neisseria meningitidis and are classified in the Carbohydrate-Active enZYmes Database as glycosyltransferase family GT-38. In this study using DNA sequence analysis and functional characterization we have identified a novel polysialyltransferase from the bovine/ovine pathogen Mannheimia haemolytica A2 (PSTMh). The enzyme was expressed in recombinant form as a soluble maltose-binding-protein fusion in parallel with the related PSTs from E. coli K1 and N. meningitidis group B in order to perform a side-by-side comparison. Biochemical properties including solubility, acceptor preference, reaction pH optima, thermostability, kinetics, and product chain length for the enzymes were compared using a synthetic fluorescent acceptor molecule. PSTMh exhibited biochemical properties that make it an attractive candidate for chemi-enzymatic synthesis applications of polysialic acid. The activity of PSTMh was examined on a model glycoprotein and the surface of a neuroprogenitor cell line where the results supported its development for use in applications to therapeutic protein modification and cell surface glycan remodelling to enable cell migration at implantation sites to promote wound healing. The three PSTs examined here demonstrated different properties that would each be useful to therapeutic applications. © 2013 Lindhout et al.

Internet of Medical Things (IoMT) platform serves as an interoperable medium for healthcare applications by connecting wearable sensors, end-users, and clinical diagnosis centers. This interoperable medium provides solutions for disease diagnosis; predicting and monitoring end-user health using physiological vital signs sensed wearable sensor data. The communicating and data exchanging internet of things (IoT) platform imposes latency and overloading uncertainties in the heterogeneous environment. This article introduces cognitive data processing for uncertainty analysis (CDP-UA) to improve WS data management's efficiency. CDP-UA addresses uncertainties in two levels namely aggregation and dissemination of WS data. The uncertainties in synchronizing aggregation and dissemination slot mapping are addressed using classification learning. In the dissemination process overloaded intervals are identified and segregated using regression learning and conditional sigmoid function analysis. The joint learning process helps to classify overloaded and latency-centric dissemination and aggregation instances to improve WS data delivery in the clinical/medical analysis center. The experimental analysis shows that the proposed method is reliable in achieving less uncertainty factor, latency, and overloaded intervals for varying disseminations and sensing intervals.