Intrinsic and Extrinsic Connections of Tet3 Dioxygenase with CXXC Zinc Finger Modules.

Tet proteins are emerging as major epigenetic modulators of cell fate and plasticity. However, little is known about how Tet proteins are targeted to selected genomic loci in distinct biological contexts. Previously, a CXXC-type zinc finger domain in Tet1 was shown to bind CpG-rich DNA sequences. Interestingly, in human and mouse the Tet2 and Tet3 genes are adjacent to Cxxc4 and Cxxc10-1, respectively. The CXXC domains encoded by these loci, together with those in Tet1 and Cxxc5, identify a distinct homology group within the CXXC domain family. Here we provide evidence for alternative mouse Tet3 transcripts including the Cxxc10-1 sequence (Tet3(CXXC)) and for an interaction between Tet3 and Cxxc4. In vitro Cxxc4 and the isolated CXXC domains of Tet1 and Tet3(CXXC) bind DNA substrates with similar preference towards the modification state of cytosine at a single CpG site. In vivo Tet1 and Tet3 isoforms with and without CXXC domain hydroxylate genomic 5-methylcytosine with similar activity. Relative transcript levels suggest that distinct ratios of Tet3(CXXC) isoforms and Tet3-Cxxc4 complex may be present in adult tissues. Our data suggest that variable association with CXXC modules may contribute to context specific functions of Tet proteins

Particle Size Distribution in Aluminum Manufacturing Facilities.

As part of exposure assessment for an ongoing epidemiologic study of heart disease and fine particle exposures in aluminum industry, area particle samples were collected in production facilities to assess instrument reliability and particle size distribution at different process areas. Personal modular impactors (PMI) and Minimicro-orifice uniform deposition impactors (MiniMOUDI) were used. The coefficient of variation (CV) of co-located samples was used to evaluate the reproducibility of the samplers. PM2.5 measured by PMI was compared to PM2.5 calculated from MiniMOUDI data. Mass median aerodynamic diameter (MMAD) and concentrations of sub-micrometer (PM1.0) and quasi-ultrafine (PM0.56) particles were evaluated to characterize particle size distribution. Most of CVs were less than 30%. The slope of the linear regression of PMI_PM2.5 versus MiniMOUDI_PM2.5 was 1.03 mg/m3 per mg/m3 (± 0.05), with correlation coefficient of 0.97 (± 0.01). Particle size distribution varied substantively in smelters, whereas it was less variable in fabrication units with significantly smaller MMADs (arithmetic mean of MMADs: 2.59 μm in smelters vs. 1.31 μm in fabrication units, p = 0.001). Although the total particle concentration was more than two times higher in the smelters than in the fabrication units, the fraction of PM10 which was PM1.0 or PM0.56 was significantly lower in the smelters than in the fabrication units (p < 0.001). Consequently, the concentrations of sub-micrometer and quasi-ultrafine particles were similar in these two types of facilities. It would appear, studies evaluating ultrafine particle exposure in aluminum industry should focus on not only the smelters, but also the fabrication facilities

Chlamydia trachomatis and the risk of spontaneous preterm birth, babies who are born small for gestational age, and stillbirth: A population-based cohort study

Background: Chlamydia trachomatis is one of the most commonly diagnosed sexually transmitted infections worldwide, but reports in the medical literature of an association between genital chlamydia infection and adverse obstetric outcomes are inconsistent. Methods: The Western Australia Data Linkage Branch created a cohort of women of reproductive age by linking records of birth registrations with the electoral roll for women in Western Australia who were born from 1974 to 1995. The cohort was then linked to both chlamydia testing records and the state perinatal registry for data on preterm births and other adverse obstetric outcomes. We determined associations between chlamydia testing, test positivity, and adverse obstetric outcomes using multivariate logistic regression analyses. Findings: From 2001 to 2012, 101558 women aged 15 to 38 years had a singleton birth. Of these women, 3921 (3·9%) had a spontaneous preterm birth, 9762 (9·6% of 101371 women with available data) had a baby who was small for gestational age, and 682 (0·7%) had a stillbirth. During their pregnancy, 21267 (20·9%) of these women had at least one chlamydia test record, and 1365 (6·4%) of those tested were positive. Before pregnancy, 19157 (18·9%) of these women were tested for chlamydia, of whom 1595 (8·3%) tested positive for chlamydia. Among all women with a test record, after adjusting for age, ethnicity, maternal smoking, and history of other infections, we found no significant association between a positive test for chlamydia and spontaneous preterm birth (adjusted odds ratio 1·08 [95% CI 0·91–1·28]; p=0·37), a baby who was small for gestational age (0·95 [0·85–1·07]; p=0·39), or stillbirth (0·93 [0·61–1·42]; p=0·74). Interpretation: A genital chlamydia infection that is diagnosed and, presumably, treated either during or before pregnancy does not substantially increase a woman’s risk of having a spontaneous preterm birth, having a baby who is small for gestational age, or having a stillbirth. Funding: Australian National Health and Medical Research Counci

Negative-index bi-anisotropic photonic metamaterial fabricated by direct laser writing and silver shadow evaporation

We present the blueprint for a novel negative-index metamaterial. This structure is fabricated via three-dimensional two-photon direct laser writing and silver shadow evaporation. The comparison of measured linear optical spectra with theory shows good agreement and reveals a negative real part of the refractive index at around 3.85 micrometer wavelength - despite the fact that the metamaterial structure is bi-anisotropic due to the lack of inversion symmetry along its surface normal.Comment: 8 pages, 3 figure

Repurposing tofacitinib as an anti-myeloma therapeutic to reverse growth-promoting effects of the bone marrow microenvironment.

The myeloma bone marrow microenvironment promotes proliferation of malignant plasma cells and resistance to therapy. Activation of JAK/STAT signaling is thought to be a central component of these microenvironment-induced phenotypes. In a prior drug repurposing screen, we identified tofacitinib, a pan-JAK inhibitor Food and Drug Administration (FDA) approved for rheumatoid arthritis, as an agent that may reverse the tumor-stimulating effects of bone marrow mesenchymal stromal cells. Herein, we validated in vitro, in stromal-responsive human myeloma cell lines, and in vivo, in orthotopic disseminated xenograft models of myeloma, that tofacitinib showed efficacy in myeloma models. Furthermore, tofacitinib strongly synergized with venetoclax in coculture with bone marrow stromal cells but not in monoculture. Surprisingly, we found that ruxolitinib, an FDA approved agent targeting JAK1 and JAK2, did not lead to the same anti-myeloma effects. Combination with a novel irreversible JAK3-selective inhibitor also did not enhance ruxolitinib effects. Transcriptome analysis and unbiased phosphoproteomics revealed that bone marrow stromal cells stimulate a JAK/STAT-mediated proliferative program in myeloma cells, and tofacitinib reversed the large majority of these pro-growth signals. Taken together, our results suggest that tofacitinib reverses the growth-promoting effects of the tumor microenvironment. As tofacitinib is already FDA approved, these results can be rapidly translated into potential clinical benefits for myeloma patients

Development of a nonlinear hierarchical model to describe the disposition of deuterium in mother-infant pairs to assess exclusive breastfeeding practice

The World Health Organization recommends exclusive breastfeeding (EBF) for the first 6 months after birth. The deuterium oxide dose-to-the-mother (DTM) technique is used to distinguish EBF based on a cut-off (< 25 g/day) of water intake from sources other than breastmilk. This value is based on a theoretical threshold and has not been verified in field studies. The aim of this study was to estimate the water intake cut-off value that can be used to define EBF practice. One hundred and twenty-one healthy infants, aged 2.5-5.5 months who were deemed to be EBF were recruited. After administration of deuterium to the mothers, saliva was sampled from mother and infant pairs over a 14-day period. Validation of infant feeding practices was conducted via home observation over six non-consecutive days with caregiver recall. A fully Bayesian framework using a gradient-based Markov chain Monte Carlo approach implemented in Stan was used to estimate the cut-off of non-milk water intake of EBF infants. From the original data set, 113 infants were determined to be EBF and provided 1500 paired mother-infant observations. The deuterium saliva concentrations were best described by two linked 1-compartment models (mother and infant), with body weight as a covariate on the mother's volume of distribution and infant's body weight on infant's water clearance rate. The cut-off value was based on the 90th percentile of the posterior distribution of non-milk water intake and was 86.6 g/day. This cut-off value can be used in future field studies in other geographic regions to determine exclusivity of breast feeding practices in order to determine their potential public health needs

Development of a parsimonious design for optimal classification of exclusive breastfeeding

A deuterium oxide dose‐to‐mother (DTM) technique is used to determine if an infant is exclusive breastfeeding (EBF). However, the DTM method is intensive, requiring seven paired mother–infant samples during a 14‐day study period. The purpose of this study was to develop a field‐friendly protocol. Data from 790 mother–infant pairs from nine countries were analyzed using a Markov chain Monte Carlo method with Stan. The data were split into (i) model building (565 pairs) and (ii) design evaluation (225 pairs). EBF classification was based on a previously published cut‐off for nonmilk water intake. Classification based on the full design was the reference (gold standard classification). The receiver operating characteristics of parsimonious designs were used to determine an optimal parsimonious classification method. The best two postdose windows (days 7–9 and 13–14) yielded optimal categorization with similar performance in the design evaluation data. This postdose two‐sample design provided 95% sensitivity and specificity when compared with the full design

Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California

The incidence and prevalence of autism have dramatically increased over the last 20 years. Decomposition of autism incidence rates into age, period and cohort effects disentangle underlying domains of causal factors linked to time trends. We estimate an age-period-cohort effect model for autism diagnostic incidence overall and by level of functioning

Duration of acute kidney injury in critically ill patients

BACKGROUND:Duration of acute kidney injury (AKI) has been recognized a risk factor for adverse outcomes following AKI. We sought to examine the relationship of AKI duration and recurrent AKI with short-term outcomes in critically ill patients who were mechanically ventilated and met criteria for the acute respiratory distress syndrome. METHODS:Participants in the NHLBI ARDS Network SAILS multicenter trial who developed AKI were included in this analysis and divided into groups based on AKI duration. Differences in outcomes were evaluated using t test and Chi-square test. Competing risks regression and Cox regression were used to evaluate factors associated with resolving AKI and recurrent AKI. RESULTS:In total, 238 patients were included in the study. Seventy-seven patients had short duration AKI (1-2 days), 47 medium duration AKI (3-7 days), 87 persistent AKI (> 7 days) and 38 died during their AKI episode. Persistent AKI was associated with worse outcomes including increased ICU length of stay, time on the ventilator and days with cardiovascular failure. We found no clinical differences between patients with short and medium duration AKI, even when accounting for AKI severity and recurrent AKI. Patients with resolving AKI were less likely to have oliguria or moderate/severe ARDS on the day AKI criteria were met. Recurrent AKI was associated with poorer clinical outcomes. No baseline clinical factors were found to predict development of recurrent AKI. CONCLUSIONS:In critically ill patients with sepsis-associated ARDS and AKI, the impact of short and medium duration AKI on clinical outcomes was modest. Persistent and recurrent AKI were both associated with worse clinical outcomes, emphasizing the importance of identifying these patients, who may benefit from novel interventions