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Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.
In this study, the pull-in phenomenon of a Nano-actuator is investigated employing a nonlocal Bernoulli-Euler beam model with clamped-clamped conditions. The model accounts for viscous damping, residual stresses, the van der Waals (vdW) force and electrostatic forces with nonlocal effects. The hybrid differential transformation/finite difference method (HDTFDM) is used to analyze the nonlocal effects on a graphene sheet nanobeam, which is electrostatically actuated under the influence of the coupling effect, the von Kármán nonlinear strains and the fringing field effect. The pull-in voltage as calculated by the presented model deviates by no more than 0.29% from previous literature, verifying the validity of the HDTFDM. Furthermore, the nonlocal nonlinear behavior of the electrostatically actuated nanobeam is investigated, and the effects of viscous damping, residual stresses, and length-gap ratio are examined in detail. Overall, the results reveal that small scale effects significantly influence the characteristics of the graphene sheet nanobeam actuator.
Oxidative stress is implicated in the etiology of schizophrenia, and the antioxidant defense system may be protective in this illness. We examined the major antioxidant glutathione (GSH) in prefrontal brain, and its correlates with clinical and demographic variables, in schizophrenia.
GSH levels were measured in the dorsolateral prefrontal region of 28 patients with chronic schizophrenia using a magnetic resonance spectroscopy sequence specifically adapted for GSH. We examined correlations of GSH levels with age, age at onset of illness, duration of illness, and clinical symptoms.
We found a negative correlation between GSH levels and age at onset (r=-.46, p=.015), and a trend-level positive relationship between GSH and duration of illness (r=.34, p=.076).
Our findings are consistent with a possible compensatory upregulation of the antioxidant defense system with longer duration of illness, and suggests the antioxidant defense system may play a role in schizophrenia.
The COllaborative project of Development of Anthropometrical measures in Twins (CODATwins) project is a large international collaborative effort to analyze individual-level phenotype data from twins in multiple cohorts from different environments. The main objective is to study factors that modify genetic and environmental variation of height, body mass index (BMI, kg/m2) and size at birth, and additionally to address other research questions such as long-term consequences of birth size. The project started in 2013 and is open to all twin projects in the world having height and weight measures on twins with information on zygosity. Thus far, 54 twin projects from 24 countries have provided individual-level data. The CODATwins database includes 489,981 twin individuals (228,635 complete twin pairs). Since many twin cohorts have collected longitudinal data, there is a total of 1,049,785 height and weight observations. For many cohorts, we also have information on birth weight and length, own smoking behavior and own or parental education. We found that the heritability estimates of height and BMI systematically changed from infancy to old age. Remarkably, only minor differences in the heritability estimates were found across cultural–geographic regions, measurement time and birth cohort for height and BMI. In addition to genetic epidemiological studies, we looked at associations of height and BMI with education, birth weight and smoking status. Within-family analyses examined differences within same-sex and opposite-sex dizygotic twins in birth size and later development. The CODATwins project demonstrates the feasibility and value of international collaboration to address gene-by-exposure interactions that require large sample sizes and address the effects of different exposures across time, geographical regions and socioeconomic status.
Antimicrobial stewardship programs typically use days of therapy to assess antimicrobial use. However, this metric does not account for the antimicrobial spectrum of activity. We applied an antibiotic spectrum index to a population of very-low-birth-weight infants to assess its utility to evaluate the impact of antimicrobial stewardship interventions.
Crystallization from solutions is a complex process completed in several stages. The first stage is the formation of supersaturated solution because the spontaneous appearance of a new phase can occur only when a system is in a nonequilibrium condition. In the next stage, molecules dissolved in solution begin to aggregate to relieve the supersaturation and move the system toward equilibrium. The molecular aggregation process eventually leads to the formation of nuclei that can act as centers of crystallization. A nucleus can be defined as the minimum amount of a new phase capable of independent existence (Khamskii 1969). The nature of nuclei (i.e., whether they are amorphous particles or tiny crystals) is still unknown. The birth of these small nuclei in an initially metastable phase is called nucleation, which is a major mechanism of first-order phase transition. Kashchiev and van Rosmalen (2003) describe nucleation as the process of fluctuational appearance of nanoscopically small clusters of the new crystalline phase, which can grow spontaneously to macroscopic sizes. The growth stage, which immediately follows nucleation, is governed by the diffusion of particles, called growth units, to the surface of the existing nuclei and their incorporation into the structure of the crystal lattice (Khamskii 1969). This stage continues until all the solute in excess of saturation is consumed for the development of mature crystals. The initial stages of crystallization, which can be defined as the period between the achievement of supersaturation and the formation of nuclei, plays a decisive role in determining properties of the resulting solid phase, such as purity, crystal structure, and particle size. Thus higher levels of control over crystallization cannot be achieved without understanding the fundamentals of nucleation.
Crystallization can be regarded as a self-assembly process in which randomly organized molecules in a fluid come together to form an ordered three-dimensional molecular array with a periodic repeating pattern. It is vital to many processes occurring in nature and manufacturing. Geologic crystallization is responsible from huge deposits of carbonates, sulfates, and phosphates that often grow in mountains and quarries. This process occurs over long periods of time, often at high temperatures and pressures, and results in large and usually highly ordered crystals such as diamond.
Learn from the experts about industrial crystallization in this third edition of a widely regarded classic that has been completely revised to reflect the latest developments in the field. New chapters on crystal nucleation, molecular modelling application, and precipitation and crystallization of pigments and dyes are included, as well as completely revised chapters on crystallization of proteins, crystallizer selection and design, control of crystallization processes, and process analytical technology. Richly illustrated with 150 new diagrams and photographs, and with dozens of practical hands-on examples, this is an ideal introduction for newcomers, and serves as an excellent reference for experienced professionals covering aspects of industrial crystallization in a single, complete volume.
Background: There is an unmet need for blood-based biomarkers that can reliably detect MS disease activity. Serum Biomarkers of interest includ Neurofilament-light-chain (NfL), Glial-fibrillary-strocyte-protein(GFAP) and Tau. Bone Marrow Transplantation (BMT) is reserved for aggressive forms of MS and has been shown to halt detectable CNS inflammatory activity for prolonged periods. Significant pre-treatment tissue damage at followed by inflammatory disease abeyance should be reflected longitudinal sera collected from these patients. Methods: Sera were collected from 23 MS patients pre-treatment, and following BMT at 3, 6, 9 and 12-months in addition from 33 non-inflammatory neurological controls. Biomarker quantification was performed with SiMoA. Results: Pre-AHSCT levels of serum NfL and GFAP but not Tau were elevated compared to controls (p=0.0001), and NfL correlated with lesion-based disease activity (6-month-relapse, MRI-T2 and Gadolinium-enhancement). 3-months post-treatment, while NfL levels remained elevated, Tau/GFAP paradoxically increased (p=0.0023/0.0017). These increases at 3m correlated with MRI ‘pseudoatrophy’ at 6-months. NfL/Tau levels dropped to that of controls by 6-months (p=0.0036/0.0159). GFAP levels dropped progressively after 6-months although even at 12-months remained higher than controls (p=0.004). Conclusions: NfL was the closest correlate of MS disease activity and treatment response. Chemotherapy-related toxicity may account for transient increases in NfL, Tau and MRI brain atrophy post-BMT.
Norovirus, a major cause of gastroenteritis in people of all ages worldwide, was first reported in South Korea in 1999. The most common causal agents of pediatric acute gastroenteritis are norovirus and rotavirus. While vaccination has reduced the pediatric rotavirus infection rate, norovirus vaccines have not been developed. Therefore, prediction and prevention of norovirus are very important. Norovirus is divided into genogroups GI–GVII, with GII.4 being the most prevalent. However, in 2012–2013, GII.17 showed a higher incidence than GII.4 and a novel variant, GII.P17-GII.17, appeared. In this study, 204 stool samples collected in 2013–2014 were screened by reverse transcriptase-polymerase chain reaction; 11 GI (5.39%) and 45 GII (22.06%) noroviruses were identified. GI.4, GI.5, GII.4, GII.6 and GII.17 were detected. The whole genomes of the three norovirus GII.17 were sequenced. The whole genome of GII.17 consists of three open reading frames of 5109, 1623 and 780 bp. Compared with 20 GII.17 strains isolated in other countries, we observed numerous changes in the protruding P2 domain of VP1 in the Korean GII.17 viruses. Our study provided genome information that might aid in epidemic prevention, epidemiology studies and vaccine development.
We present an account of why we decided to retract a paper. We discovered a lack of adherence to conventional trials registration, execution, interpretation and reporting, and consequently, with the authors, needed to correct the scientific record. We set out our responses in general to strengthen research integrity.
Declaration of interest
K.S.B. is Editor-in-Chief of the British Journal of Psychiatry. W.L., K.R.K. and S.M.L. are members of the senior editorial committee and the research integrity committee for the journal. In the past three years, S.M.L. has received research support from Janssen and Lundbeck, and personal support from Janssen, Otsuka and Sunovion.