Miracle-dz/UniFAR-FTUs huggingface dataset:
Congenital disorders of glycosylation: sweet news

Purpose of review Congenital disorders of glycosylation (CDG) have grown enormously since the discovery of the first protein glycosylation defect in 1980, presenting with a broad clinical spectrum. Expansion in number and complexity of the CDG group has even necessitated a new nomenclature. By 2011, the CDG group includes lipid glycosylation disorders and other related processes and almost 50 distinct disorders. Recent findings Current research has not only expanded the spectrum of CDG types, but has also given novel insight into those previously described. The discovery of genetic defects in the conserved oligomeric Golgi complex, affecting protein glycosylation and processing through the secretory pathway, raised the concept of ‘secondary’ glycosylation disorders. The number of lipid glycosylation disorders, linking lipid synthesis to CDG, that were previously regarded as rare, is also increasing rapidly. In other areas of research, the bridge between muscular dystrophies and metabolic disorders is being further reinforced with the discovery of additional defects in the DPM-CDG subgroup, a CDG characterized by significant muscle involvement. Summary It is of great importance that clinicians stay up-to-date on the field of CDG and consider it in their differential diagnosis of unknown syndromal presentations. Nevertheless, many advances have yet to be made, including information on the natural course of CDG. The lack of treatment for nearly all CDG types is striking, and the field must continue to push for innovative therapies. Clinicians and researchers must work together to describe the natural course and, most importantly, collaborate to find new therapies.
Ssd1p of Saccharomyces cerevisiae Associates with RNA*

The SSD1 gene has been isolated as a single copy suppressor of many mutants, such as sit4,slk1/bck1, pde2, and rpc31, in the yeast Saccharomyces cerevisiae. Ssd1p has domains showing weak but significant homology with RNase II-related proteins, Cyt4p, Dss1p, VacB, and RNase II, which are involved in the modification of RNA. We found that Ssd1p had the ability to bind RNA, preferably poly(rA), as well as single-stranded DNA. Interestingly, the most conserved domain among the RNase II-related proteins was not necessary for interaction with RNA. Indirect immunofluorescence staining with anti-Ssd1p antibody revealed that Ssd1p was detected mainly in the cytoplasm. Furthermore, sucrose gradient sedimentation analysis demonstrated that Ssd1p was not cofractionated with polyribosomes, suggesting that Ssd1p is not particularly bound to a translationally active subpopulation of mRNA in the cytoplasm.
Cutting Edge: In Vivo Induction of Integrated HIV-1 Expression by Mycobacteria Is Critically Dependent on Toll-Like Receptor 2 1

Mycobacterial infection has been implicated as a possible factor in AIDS progression in populations where HIV-1 and Mycobacterium tuberculosis are coendemic. In support of this concept, we have previously shown that HIV-1-transgenic (Tg) mice infected with mycobacteria display enhanced viral gene and protein expression. In this study, we demonstrate that the induction of HIV-1 observed in this model is dependent on Toll-like receptor 2 (TLR2), a pattern recognition receptor known to be involved in mycobacteria-host interaction. Spleen cells from HIV-1-Tg mice deficient in TLR2 (Tg/TLR2−/−) were found to be completely defective in p24 production induced in response to live M. tuberculosis or Mycobacterium avium as well as certain mycobacterial products. Importantly, following in vivo mycobacterial infection, Tg/TLR2−/− mice failed to display the enhanced HIV-1 gag/env mRNA and p24 protein synthesis exhibited by wild-type Tg animals. Together, these results argue that TLR2 plays a crucial role in the activation of HIV-1 expression by mycobacterial coinfections.
Differential response of cultured human umbilical vein and artery endothelial cells to Ah receptor agonist treatment: CYP-dependent activation of food and environmental mutagens.

In the present study, 7-ethoxyresorufin O-deethylase (EROD), 7, 12-dimethylbenz[a]anthracene (DMBA)-hydroxylase, and covalent binding of (3)H-labeled 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole ((3)H-Trp-P-1) and (3)H-DMBA were examined in human umbilical vein endothelial cells (HUVEC) and human umbilical artery endothelial cells (HUAEC) exposed to the aryl hydrocarbon (Ah) receptor agonist beta-naphthoflavone (BNF) or vehicle only. The results revealed a marked induction of enzymatic activity in BNF-treated HUVEC compared with vehicle-treated cells, whereas no similar response was observed in BNF-treated HUAEC. EROD, DMBA hydroxylase, and covalent binding of (3)H-Trp-P-1 and (3)H-DMBA in BNF-treated HUVEC were reduced in the presence of the CYP1A inhibitor ellipticine. Addition of other CYP1A inhibitors alpha-naphthoflavone, miconazole, 1-ethynylpyrene, 1-(1-propynyl)pyrene), or the CYP1A substrate ethoxyresorufin to the incubation buffer of BNF-treated HUVEC reduced covalent binding of (3)H-Trp-P-1 by 93-98%. Western blot analysis confirmed an induction of CYP1A1 in BNF-treated HUVEC, but not in BNF-treated HUAEC. CYP1A1 was, however, detected in both vehicle- and BNF-treated HUAEC. The results showed that BNF exposure induced CYP1A1 and metabolic activation of xenobiotics in HUVEC, whereas the catalytic activity remained low in BNF-treated HUAEC. Our results suggest that endothelial lining of human veins may be a target for adverse effects of xenobiotics activated into reactive metabolites by Ah receptor-regulated enzymes. Several studies have detected CYP1A1 in endothelial linings, whereas expression of CYP1A2 and CYP1B1 seems to be negligible at this site. This suggests that the metabolic activation and covalent binding of (3)H-Trp-P-1 and (3)H-DMBA in HUVEC are most likely mediated by CYP1A1.
Effect of Intratympanic Application of Aminoglycosides on Click-Evoked Myogenic Potentials in Guinea Pigs

Objectives: Although numerous studies have identified damage to the cochlear and vestibular end organs as the primary site of aminoglycoside-induced ototoxicity, the effect on the saccule remains poorly understood, possibly due to lack of monitoring saccular function in experimental animals. Therefore, this study applied three kinds of aminoglycosides into the tympanic space of guinea pigs to examine their toxic impact on the saccule by way of click-evoked myogenic potential test coupled with morphologic assessment. Design: Albino guinea pigs were treated with saline, gentamicin, tobramycin, or amikacin, with 10 animals assigned to each group. Each compound was injected directly overlying but not through the round window membrane on the left ear, with the right ear serving as a control. One week after injection, each animal underwent auditory brain stem response, caloric test, and click-evoked myogenic potential test. Animals were then killed for morphologic assessment through the use of light and electron microscopic examinations. Results: The animals treated with saline, gentamicin, tobramycin, or amikacin exhibited abnormal auditory brain stem response in 0%, 30%, 100%, and 30% of cases; abnormal caloric responses were found in 0%, 100%, 40%, and 40% of cases; absent click-evoked myogenic potentials were found in 0%, 100%, 30%, and 40% of cases, respectively. Gentamicin and other groups differed significantly in abnormal rates of caloric responses and click-evoked myogenic potentials. Morphologic study of the gentamicin-treated animals confirmed that the absence of click-evoked myogenic potential originated from the lesion in the saccular macula. Conclusions: Gentamicin represents the dominant susceptibility of aminoglycoside-induced vestibulotoxicity for eliminating both semicircular canal and saccular functions. This study further confirms the findings of human studies in which the caloric and vestibular evoked myogenic potentials responses were monitored to assess the abolition of vestibular function in patients treated with intratympanic gentamicin injection.
Complementary expression pattern of Zfhx1 genes Sip1 and δEF1 in the mouse embryo and their genetic interaction revealed by compound mutants

In mouse embryos, the Zfhx1 transcription factor genes, Sip1 and δEF1, are expressed in complementary domains in many tissues. Their possible synergism in embryogenesis was investigated by comparing the phenotype of Sip1−/−;δEF1−/− double homozygotes with single homozygous embryos. Unexpectedly, in Sip1−/− embryos δEF1 was ectopically activated, suggesting a negative regulation of δEF1 expression by Sip1. Sip1−/−;δEF1−/− embryos were similar to Sip1−/− embryos in short somite production and developmental arrest around E8.5, but showed more severe defects in dorsal neural tube morphogenesis accompanied by a larger reduction of Sox2 expression, ascribable to the loss of the ectopic δEF1 expression. Sip1+/−;δEF1−/− embryos develop various morphological defects after E10 that were absent in δEF1−/− embryos even in tissues without significant overlap of Sip1 and δEF1 expression, and arrested during mid gestation earlier than δEF1−/− embryos. These findings indicate that complex synergistic interactions occur between Zfhx1 transcription factor genes during mouse embryogenesis. Developmental Dynamics 235:1941–1952, 2006. © 2006 Wiley‐Liss, Inc.
The BEL1-type homeobox gene SH5 induces seed shattering by enhancing abscission-zone development and inhibiting lignin biosynthesis.

Seed shattering is an important trait that influences grain yield. A major controlling quantitative trait locus in rice is qSH1. Although the degree of shattering is correlated with the level of expression of qSH1, some qSH1-defective cultivars display moderate shattering while others show a non-shattering phenotype. Os05 g38120 (SH5) on chromosome 5 is highly homologous to qSH1. Although we detected SH5 transcripts in various organs, this gene was highly expressed at the abscission zone (AZ) in the pedicels. When expression of this gene was suppressed in easy-shattering 'Kasalath', development of the AZ was reduced and thereby so was seed loss. By contrast, the extent of shattering, as well as AZ development, was greatly enhanced in moderate-shattering 'Dongjin' rice when SH5 was overexpressed. Likewise, overexpression of SH5 in the non-shattering 'Ilpum' led to an increase in seed shattering because lignin levels were decreased in the basal region of spikelets in the absence of development of an AZ. We also determined that two shattering-related genes, SHAT1 and Sh4, which are necessary for proper formation of an AZ, were induced by SH5. Based on these observations, we propose that SH5 modulates seed shattering by enhancing AZ development and inhibiting lignin biosynthesis.
B chromosomes in Sternorrhyncha (Hemiptera, Insecta)

In the hemipteroid insects of the suborder Sternorrhyncha, B chromosomes are relatively common in comparison with other suborders of Hemiptera. However, the occurrence of supernumerary chromosomes is restricted, in most cases, to several genera or closely related species. At least in some species of Psylloidea with the XY sex determination system, a mitotically stable B chromosome integrated into an achiasmatic segregation system with the X, and became fixed as a Y chromosome. In some Aphidoidea with a multiple X system of sex determination, B chromosomes appear to be in fact non-functional X chromosomes. Supernumerary chromosomes thus probably play an important role in the evolution of sex determination systems in Sternorrhyncha.
Variants in KCNQ1, AP3S1, MAN2A1, and ALDH7A1 and the risk of type 2 diabetes in the Chinese Northern Han population: a case-control study and meta-analysis.

BACKGROUND Recent studies have explored several novel type 2 diabetes (T2D) susceptibility variants in the KCNQ1 (rs2237892), AP3S1 (rs3756555), MAN2A1 (rs2015698), and ALDH7A1 (rs2306617) genes in Japan and Western Africa. The aim here was to evaluate the contribution of variants in these genes to predisposition for T2D in the Chinese Northern Han population. MATERIAL/METHODS Four candidate single-nucleotide polymorphisms (rs2237892, rs2306617, rs2015698, and rs3756555) were selected and genotyped in 537 unrelated individuals with type 2 diabetes and 510 normal controls. A meta-analysis was also done to explore the association of rs2237892 with T2D in this population. RESULTS The C risk allele in rs2237892 and rs3756555 conferred significantly increased susceptibility to T2D (p=0.001, p=0.003, respectively). The significant association remained after adjusting the age, sex, and BMI (OR=1.40, 95%CI: 1.16-1.69, p=0.001; OR=1.35 95%CI: 1.11-1.63, p=0.002). No association was observed in any genetic models for rs2015698 and rs2306617. Further investigation of the control subjects using an additive model showed that fasting plasma glucose was significantly higher in the individuals with the CC genotype of rs2237892 than in those with the other two genotypes after adjusting for age, sex, and BMI (beta=0.062 mmol/l per risk allele, p=0.008). The SNP of rs3756555 was marginally associated with BMI in a recessive model (p=0.05). Meta-analysis yielded an OR of 1.36 (95%CI: 1.23-1.51) for rs2237892. CONCLUSIONS In this study the effects of KCNQ1 and AP3S1 variants on susceptibility to T2D in the Chinese Northern Han population were confirmed.
Many Class I Integrons Comprise Distinct Stable Structures Occurring in Different Species ofEnterobacteriaceae Isolated from Widespread Geographic Regions in Europe

ABSTRACT Three sizes of inserted regions of DNA (800, 1,000, and 1,500 bp) were shown to be common among class I integrons in unrelated clinical isolates of Enterobacteriaceae from different European hospitals. Sequencing showed that 800-bp inserted regions comprised identical sequences including aacA4, that 1,000-bp inserted regions included aadA, and that 1,500-bp inserted regions included dfrI and aadA1, irrespective of host species and geographic origin. In addition promoter sequences were mostly identical for each size class. These data suggest that inserted gene cassettes and promoter regions of integrons are conserved and stable, with resistance genes transferred more often as part of the entire integron structure than as individual gene cassettes.
Prenatal cigarette smoke exposure and postnatal respiratory responses to hypoxia and hypercapnia

Prenatal cigarette smoke (CS) exposure, in combination with hypoxia and/or hyperthermia can lead to gasping and attenuated recovery from hypoxia in 7 days old rat pups. We studied 95 unanesthetized spontaneously breathing 14 days old rat pups to investigate if the destabilizing effects of increased ambient temperature and prenatal CS exposure on respiratory control observed in 7 days old rats were still evident at day 14. This postnatal age was selected as it is beyond the analogous risk period for SIDS in human. Furthermore, we investigated if the breathing responses to hypercapnia are affected by prenatal CS exposure. Since high ambient (HA) temperature can lead to gasping and aberrant respiratory control, we recorded respiratory patterns at low (24–25°C) and high (29–30°C) ambient temperatures, and under hypoxic or hypercapnic states. No gasping was observed in 14 days old rat pups. During hypoxia, breathing frequency increased in the CS‐exposed group under low and HA temperatures. Rectal temperature decreased only in the sham group in response to low ambient temperature hypoxia. At HA temperature, breathing frequency increased in both sham and CS‐exposed groups during hypercapnia, however, it remained elevated during washout period only in the sham group. We demonstrate that prenatal CS exposure continues to have profound effects on respiratory and thermoregulatory responses to hypoxia and hypercapnia at day 14. The attenuated respiratory and thermoregulatory responses to acute hypoxia and hypercapnia on day 14 demonstrate a strong interaction between CS exposure, respiratory control, and thermoregulation during postnatal maturation. Pediatr Pulmonol. 2012; 47:487–497. © 2011 Wiley Periodicals, Inc.
5-HT3 antagonists under development

Importance of the field: The main therapeutic area of 5-HT3 receptor antagonists is the treatment of chemotherapy-induced nausea and vomiting (CINV), which is the most common and distressing side effects of anticancer treatment. The second major clinical application of 5-HT3 receptor antagonists is in the treatment of irritable bowel syndrome (IBS). 5-HT3 antagonists have been widely used and found to decrease gut transit, increase fluid absorption and reduce pain. The uses of 5-HT3 antagonists are expending to treatment of CNS diseases such as anxiety and sleep disorders as antipsychotics and so on. Areas covered in this review: The structures, in vitro activities, in vivo effects and some clinical data on 5-HT3 receptor antagonists under development. What the reader will gain: Future research directions in 5-HT3 antagonists based on the clinical trial data of the pipeline molecules. Take home message: Most drug candidates in clinical trials were discovered in the early 1990s and their patent expiry is imminent. Acquiring intellectual properties of novel 5-HT3 receptor antagonists with improved efficacies would provide a bright future. Particularly, as the current 5-HT3 receptor antagonists are classified into only three representative structural families (one third are zacopride-like benzamides and the others are ondansteron-like tricyclic compounds and dolansetron-like bicyclic compounds), structurally diverse compound libraries need to be extensively investigated for identification of novel 5-HT3 receptor antagonists.
Measurement of subclinical atherosclerosis: beyond risk factor assessment

Purpose of review Assessment of subclinical atherosclerosis using the current available noninvasive imaging modalities holds promise for individual cardiovascular risk management and monitoring efficacy of therapeutic interventions (i.e. surrogate end-points). The present review addresses benefits and limitations of flow-mediated dilatation, intima-media thickness, electron-beam computed tomography and magnetic resonance coronary angiography. Recent findings Both carotid intima-media thickness and peripheral flow-mediated dilatation correlate inversely with cardiovascular risk factors and coronary artery disease. They have been shown to carry predictive value for future cardiovascular events, but clinical application of both intima-media thickness and flow-mediated dilatation demands further methodological maturation of these techniques. Intima thickening has been successfully targeted in numerous intervention trials, but determination of an explicit threshold value beyond which cardiovascular risk significantly increases will facilitate its utility as a routine clinical tool. Electron-beam computed tomography can accurately detect and quantify coronary artery calcification (an established marker of the total coronary plaque burden). However, lack of evidence of its additional predictive power for future coronary events warrants for further research. Finally, magnetic resonance coronary angiography appears to be a promising technique, integrating both functional and anatomical aspects of coronary artery disease. Properly designed studies are needed to determine its value in clinical practice. Summary Various noninvasive imaging techniques have recently emerged that may find applications in clinical research. However, before widespread clinical utilization, further technical refinement of all of the cited imaging modalities is mandatory. It will be a challenge over the coming few years to clarify whether improvements in surrogate end-points can directly be translated into improved outcomes.
Mathematical analysis of ligand-induced monomerization and dimerization in the monomer dimer equilibrium of proteins. Application to D-amino acid oxidase.

We have mathematically analyzed ligand-induced monomerization and dimerization in a protein monomer-dimer equilibrium system, in which the monomer has one and the dimer two binding sites. These dimer sites have the same binding constants for the first ligand but may cooperatively interact when one of them is occupied by a ligand molecule. In this system, the apparent dimerization constant and the apparent molecular weight are functions of free ligand concentration, and depend on the intrinsic binding constants of the ligand molecule to the monomer and the dimer. The behavior of these functions is classified into 17 cases according to the values of the three intrinsic binding constants, and some calculated examples are shown graphically for selected parameters. The theory was also applied to D-amino acid oxidase [EC 1.4. 3.3], a flavoprotein, and the pH dependence of the apparent dimerization constant and the apparent molecular weight in the presence of ligand, p-aminobenzoate, were studied theoretically using parameters obtained in our previous experiments (5).
Structural Characterization of PTX3 Disulfide Bond Network and Its Multimeric Status in Cumulus Matrix Organization*

PTX3 is an acute phase glycoprotein that plays key roles in resistance to certain pathogens and in female fertility. PTX3 exerts its functions by interacting with a number of structurally unrelated molecules, a capacity that is likely to rely on its complex multimeric structure stabilized by interchain disulfide bonds. In this study, PAGE analyses performed under both native and denaturing conditions indicated that human recombinant PTX3 is mainly composed of covalently linked octamers. The network of disulfide bonds supporting this octameric assembly was resolved by mass spectrometry and Cys to Ser site-directed mutagenesis. Here we report that cysteine residues at positions 47, 49, and 103 in the N-terminal domain form three symmetric interchain disulfide bonds stabilizing four protein subunits in a tetrameric arrangement. Additional interchain disulfide bonds formed by the C-terminal domain cysteines Cys317 and Cys318 are responsible for linking the PTX3 tetramers into octamers. We also identified three intrachain disulfide bonds within the C-terminal domain that we used as structural constraints to build a new three-dimensional model for this domain. Previously it has been shown that PTX3 is a key component of the cumulus oophorus extracellular matrix, which forms around the oocyte prior to ovulation, because cumuli from PTX3-/- mice show defective matrix organization. Recombinant PTX3 is able to restore the normal phenotype ex vivo in cumuli from PTX3-/- mice. Here we demonstrate that PTX3 Cys to Ser mutants, mainly assembled into tetramers, exhibited wild type rescue activity, whereas a mutant, predominantly composed of dimers, had impaired functionality. These findings indicate that protein oligomerization is essential for PTX3 activity within the cumulus matrix and implicate PTX3 tetramers as the functional molecular units required for cumulus matrix organization and stabilization.
Using automated tests for communicating and verifying non-functional requirements

In software development the code often must comply to a number of non-functional requirements, like architectural requirements. These requirements are often communicated and verified by writing guidelines and creating reports of the non-compliance. This way of communicating and verifying non-functional requirements is very costly since all developers needs to understand all requirements. It is also very hard for a developer to remember all requirements and it is easy to make mistakes. In software development much of the work is done in a tool-chain. The tool-chain contains tools like text editors, compilers, linkers, static analysis tools, automatic test frameworks etc. An alternative way to communicate and verify non-functional requirements is to add them to the tool-chain as automated tests and checkers, so the developers get fast automated feedback when they do mistakes. I have worked many years as a software architect defining and writing architectural requirements and my observations and experiences shows that the productivity is increased and number of non-compliant non-functional requirements is lower using the tool-chain feedback instead of using guidelines and reports.