Introducing BITTSy: The Behavioral Infant & Toddler Testing System.

This manuscript introduces BITTSy, the Behavioral Infant & Toddler Testing System. This software system is capable of running the headturn preference procedure, preferential looking, conditioned headturn, and visual fixation/habituation procedures. It uses only commercial-off-theshelf (COTS) hardware to implement the procedures in an affordable and space-efficient setup. The software package, example protocols and data sets, and manual are freely available and downloadable from go.umd.edu/BITTSy, making this entire set of procedures available to resource-limited labs. Researchers can easily use BITTSy at multiple sites in a uniform manner, resulting in a standardized, powerful research tool that can enhance cross-site research collaborations.

Is the timed loaded standing test a valid measure of back muscle endurance in people with vertebral osteoporosis?

Timed loaded standing (TLS) is a suggested measure of back muscle endurance for people with vertebral osteoporosis. Surface electromyography revealed back muscles work harder and fatigue during TLS. The test end-point and total time were associated with back fatigue. The findings help demonstrate the concurrent validity of the TLS test. INTRODUCTION: The TLS test is suggested as a measure of back muscle endurance for patients with vertebral osteoporosis. However, to date, no study has demonstrated that TLS does measure back extensor or erector spinae (ES) muscle endurance. We used surface electromyography (sEMG) to investigate the performance of the thoracic ES muscles during TLS. METHODS: Thirty-six people with vertebral osteoporosis with a mean age of 71.6 (range 45-86) years participated. sEMG recordings were made of the ES at T3 and T12 bilaterally during quiet standing (QS) and TLS. The relative (%) change in sEMG amplitude between conditions was compared. Fatigue was evaluated by analysing the change in median frequency (MF) of the sEMG signal during TLS, and the correlation between maximal TLS time and rate of MF decline was examined. RESULTS: Activity in the ES increased significantly during TLS at all electrode locations. During TLS, the MF declined at a mean rate of -24.2% per minute (95% C.I. -26.5 to -21.9%). The MF slope and test time were strongly correlated (r2 = 0.71), and at test end, the final MF dropped to an average 89% (95% C.I. 85 to 93%) of initial MF. Twenty-eight participants (78%) reported fatigue was the main reason for stopping, and for eight (22%), it was pain. CONCLUSIONS: This study demonstrates that TLS challenges the ES muscles in the thoracic region and results in ES fatigue. Endurance time and the point at which the TLS test ends are strongly related to ES fatigue.

Estimating gestational age at birth from fundal height and additional anthropometrics: a prospective cohort study.

OBJECTIVE: Accurate assessment of gestational age (GA) is critical to paediatric care, but is limited in developing countries without access to ultrasound. Our objectives were to assess the accuracy of prediction of GA at birth and preterm birth classification using routinely collected anthropometry measures. DESIGN: Prospective cohort study. SETTING: United States. POPULATION OR SAMPLE: A total of 2334 non-obese and 468 obese pregnant women. METHODS: Enrolment GA was determined based on last menstrual period, confirmed by first-trimester ultrasound. Maternal anthropometry and fundal height (FH) were measured by a standardised protocol at study visits; FH alone was additionally abstracted from medical charts. Neonatal anthropometry measurements were obtained at birth. To estimate GA at delivery, we developed three predictor models using longitudinal FH alone and with maternal and neonatal anthropometry. For all predictors, we repeatedly sampled observations to construct training (60%) and test (40%) sets. Linear mixed models incorporated longitudinal maternal anthropometry and a shared parameter model incorporated neonatal anthropometry. We assessed models' accuracy under varied scenarios. MAIN OUTCOME MEASURES: Estimated GA at delivery. RESULTS: Prediction error for various combinations of anthropometric measures ranged between 13.9 and 14.9 days. Longitudinal FH alone predicted GA within 14.9 days with relatively stable prediction errors across individual race/ethnicities [whites (13.9 days), blacks (15.1 days), Hispanics (15.5 days) and Asians (13.1 days)], and correctly identified 75% of preterm births. The model was robust to additional scenarios. CONCLUSIONS: In low-risk, non-obese women, longitudinal FH measures alone can provide a reasonably accurate assessment of GA when ultrasound measures are not available. TWEETABLE ABSTRACT: Longitudinal fundal height alone predicts gestational age at birth when ultrasound measures are unavailable.

A splice site variant in the SUV39H2 gene in Greyhounds with nasal parakeratosis.

Hereditary nasal parakeratosis (HNPK), described in the Labrador Retriever breed, is a monogenic autosomal recessive disorder that causes crusts and fissures on the nasal planum of otherwise healthy dogs. Our group previously showed that this genodermatosis may be caused by a missense variant located in the SUV39H2 gene encoding a histone 3 lysine 9 methyltransferase, a chromatin modifying enzyme with a potential role in keratinocyte differentiation. In the present study, we investigated a litter of Greyhounds in which six out of eight puppies were affected with parakeratotic lesions restricted to the nasal planum. Clinically and histologically, the lesions were comparable to HNPK in Labrador Retrievers. Whole genome sequencing of one affected Greyhound revealed a 4-bp deletion at the 5'-end of intron 4 of the SUV39H2 gene that was absent in 188 control dog and three wolf genomes. The variant was predicted to disrupt the 5'-splice site with subsequent loss of SUV39H2 function. The six affected puppies were homozygous for the variant, whereas the two non-affected littermates were heterozygous. Genotyping of a larger cohort of Greyhounds revealed that the variant is segregating in the breed and that this breed might benefit from genetic testing to avoid carrier × carrier matings.

RNA binding proteins as regulators of immune cell biology.

Sequence-specific RNA binding proteins (RBP) are important regulators of the immune response. RBP modulate gene expression by regulating splicing, polyadenylation, localization, translation and decay of target mRNAs. Increasing evidence suggests that RBP play critical roles in the development, activation and function of lymphocyte populations in the immune system. This review will discuss the post-transcriptional regulation of gene expression by RBP during lymphocyte development, with particular focus on the Tristetraprolin family of RBP.

Self-assembly of a space-tessellating structure in the binary system of hard tetrahedra and octahedra.

We report the formation of a binary crystal of hard polyhedra due solely to entropic forces. Although the alternating arrangement of octahedra and tetrahedra is a known space-tessellation, it had not previously been observed in self-assembly simulations. Both known one-component phases - the dodecagonal quasicrystal of tetrahedra and the densest-packing of octahedra in the Minkowski lattice - are found to coexist with the binary phase. Apart from an alternative, monoclinic packing of octahedra, no additional crystalline phases were observed.

Correction: Self-assembly of a space-tessellating structure in the binary system of hard tetrahedra and octahedra.

Correction for 'Self-assembly of a space-tessellating structure in the binary system of hard tetrahedra and octahedra' by A. T. Cadotte et al., Soft Matter, 2016, DOI: .

First-in-human study of pbi-05204, an oleander-derived inhibitor of akt, fgf-2, nf-κΒ and p70s6k, in patients with advanced solid tumors.

BACKGROUND: PBI-05204, a Nerium oleander extract (NOE) containing the cardiac glycoside oleandrin, inhibits the α-3 subunit of Na-K ATPase, as well as FGF-2 export, Akt and p70S6K, hence attenuating mTOR activity. This first-in-human study determined the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of PBI-05204 in patients with advanced cancer. Methods Forty-six patients received PBI-05204 by mouth for 21 of 28 days (3 + 3 trial design). Dose was escalated 100% using an accelerated titration design until grade 2 toxicity was observed. Plasma PK and mTOR effector (p70S6K and pS6) protein expressions were evaluated. Results Dose-limiting toxicities (grade 3 proteinuria, fatigue) were observed at dose level 8 (0.3383 mg/kg/day). Common possible drug-related adverse were fatigue (26 patients, 56.5%), nausea (19 patients, 41.3%) and diarrhea (15 patients, 32.6 %). Electrocardiogram monitoring revealed grade 1 atrioventricular block (N = 10 patients) and grade 2 supraventricular tachycardia (N = 1). The MTD was DL7 (0.2255 mg/kg) where no toxicity of grade ≥ 3 was observed in seven patients treated. Seven patients (15%) had stable disease > 4 months. Mean peak oleandrin concentrations up to 2 ng/mL were achieved, with area under the curves 6.6 to 25.5 µg/L*hr and a half-life range of 5-13 h. There was an average 10% and 35% reduction in the phosphorylation of Akt and pS6 in PBMC samples in 36 and 32 patients, respectively, tested between predose and 21 days of treatment. Conclusions PBI-05204 was well tolerated in heavily pretreated patients with advanced solid tumors. The recommended Phase II dose is 0.2255 mg/kg/day.

The Gray Institute 'open' high-content, fluorescence lifetime microscopes.

We describe a microscopy design methodology and details of microscopes built to this 'open' design approach. These demonstrate the first implementation of time-domain fluorescence microscopy in a flexible automated platform with the ability to ease the transition of this and other advanced microscopy techniques from development to use in routine biology applications. This approach allows easy expansion and modification of the platform capabilities, as it moves away from the use of a commercial, monolithic, microscope body to small, commercial off-the-shelf and custom made modular components. Drawings and diagrams of our microscopes have been made available under an open license for noncommercial use at http://users.ox.ac.uk/~atdgroup. Several automated high-content fluorescence microscope implementations have been constructed with this design framework and optimized for specific applications with multiwell plates and tissue microarrays. In particular, three platforms incorporate time-domain FLIM via time-correlated single photon counting in an automated fashion. We also present data from experiments performed on these platforms highlighting their automated wide-field and laser scanning capabilities designed for high-content microscopy. Devices using these designs also form radiation-beam 'end-stations' at Oxford and Surrey Universities, showing the versatility and extendibility of this approach.

PDBe: Protein Data Bank in Europe.

The Protein Data Bank in Europe (PDBe) (http://www.ebi.ac.uk/pdbe/) is actively working with its Worldwide Protein Data Bank partners to enhance the quality and consistency of the international archive of bio-macromolecular structure data, the Protein Data Bank (PDB). PDBe also works closely with its collaborators at the European Bioinformatics Institute and the scientific community around the world to enhance its databases and services by adding curated and actively maintained derived data to the existing structural data in the PDB. We have developed a new database infrastructure based on the remediated PDB archive data and a specially designed database for storing information on interactions between proteins and bound molecules. The group has developed new services that allow users to carry out simple textual queries or more complex 3D structure-based queries. The newly designed 'PDBeView Atlas pages' provide an overview of an individual PDB entry in a user-friendly layout and serve as a starting point to further explore the information available in the PDBe database. PDBe's active involvement with the X-ray crystallography, Nuclear Magnetic Resonance spectroscopy and cryo-Electron Microscopy communities have resulted in improved tools for structure deposition and analysis.

An NSF function distinct from ATPase-dependent SNARE disassembly is essential for Golgi membrane fusion.

The precise biochemical role of N-ethylmaleimide-sensitive factor (NSF) in membrane fusion mediated by SNARE proteins is unclear. To provide further insight into the function of NSF, we have introduced a mutation into mammalian NSF that, in Drosophila dNSF-1, leads to temperature-sensitive neuroparalysis. This mutation is like the comatose mutation and renders the mammalian NSF temperature sensitive for fusion of postmitotic Golgi vesicles and tubules into intact cisternae. Unexpectedly, at the temperature that is permissive for membrane fusion, this mutant NSF binds to, but cannot disassemble, SNARE complexes and exhibits almost no ATPase activity. A well-charaterized NSF mutant containing an inactivating point mutation in the catalytic site of its ATPase domain is equally active in the Golgi-reassembly assay. These data indicate that the need for NSF during postmitotic Golgi membrane fusion may be distinct from its ATPase-dependent ability to break up SNARE pairs.

P-24: a human leukemia-associated and lymphohemopoietic progenitor cell surface structure identified with monoclonal antibody.

This study was directed at surface structures that are found on human lymphohemopoietic progenitor cells in normal and leukemic bone marrow. A monoclonal antibody was produced against an acute lymphoblastic leukemia (ALL) cell line of the pre-B phenotype; this antibody (BA-2) was used to demonstrate a cell surface polypeptide of approximately 24,000 mol wt that migrates similarly in both reduced and nonreduced form. This polypeptide, p24/BA-2, was shown by immune precipitation and gel electrophoresis and cell distribution studies to be different from HLA-DR and gp 100/cALLa. p24/BA-2 was present on the surface of 77% (54/70) of cases of non-T, non-B ALL; BA-2 staining was less bright or nondetectable in surface Ig+ (SIg+) chronic lymphocytic leukemia (CLL) and T ALL and nondetectable on peripheral T and B lymphocytes. Approximately 3% of bone marrow mononuclear cells were p24/BA-2+, and these cells were E rosette-, surface (SIg-), and nonphagocytic. Marrow TdT+ progenitor cells were frequently p 24/BA-2+. Results suggest that p24/BA-2 represents a surface structure present on lymphohemopoietic bone marrow progenitor cells and that most common types of ALL bear the p25/BA-2 structure.

Design, construction and characterisation of a portable gamma-ray spectrometer for low-level natural occurring radioactive material ex-situ measurement.

The activity concentrations in naturally occurring radioactive material (NORM) samples are conventionally measured using a gamma-ray spectrometer with a single detector (mostly HPGe or NaI:Tl) enclosed in a lead shield. In this work, a passive water shield to reduce background radiation reaching the detectors was designed using GEANT4-toolkit Monte Carlo simulations and then constructed. This measurement system is portable and cost-effective for ex-situ measurements. IAEA-375 soil and beach sand each placed in Marinelli beakers were measured using two LaBr3:Ce detectors in singles and coin-cidence modes. A novel method of background reduction by using photon time-of-flight was employed together with the measurement of the two photons energies. These samples were also measured in singles mode using a NaI:Tl detector inside the constructed water shield and HPGe detector shielded with lead to compare and validate the results of LaBr3:Ce detectors measurement. Both the simulated and measured results show that the water shield (500 mm thick) attenuates 2614.5 keV gamma rays by 90 %. The minimum detectable activity (MDA) measured for 24 h using the NaI:Tl detector without shield and inside the water shield are; 546 Bq kg-1 and 146 Bq kg-1 at 1460.8 keV (40K), 194 Bq kg-1 and 15 Bq kg-1 at 1764.5 keV (238U series), and 131 Bq kg-1 and 15 Bq kg-1 at 911.2 keV (232Th series), respectively. The measured activity concentrations of 238U and 232Th series and 40K radionuclides inside IAEA-375 soil agree with certified values to within measurement uncertainties. The measured activity of 138La in the LaBr3:Ce detector crystal is 263.8 ± 26.8 Bq kg-1. The internal activity of the LaBr3:Ce detector increases the MDA at 1460.8 keV and 2614.5 keV, which limits the measurement of primordial radionuclides with low activity concentration in singles mode. The activity concentrations of 238U and 232Th series radionuclides in beach sand were measured using NaI:Tl and LaBr3:Ce detectors. The results are consistent with those from HPGe measurement to within uncertainties.

Enabling near-atomic-scale analysis of frozen water.

Transmission electron microscopy went through a revolution enabling routine cryo-imaging of biological and (bio)chemical systems, in liquid form. Yet, these approaches typically lack advanced analytical capabilities. Here, we used atom probe tomography to analyze frozen liquids in three dimensions with subnanometer resolution. We introduce a specimen preparation strategy using nanoporous gold. We report data on 2- to 3-µm-thick layers of ice formed from both high-purity deuterated water and a solution of 50 mM NaCl in high-purity deuterated water. The analysis of the gold-ice interface reveals a substantial increase in the solute concentrations across the interface. We explore a range of experimental parameters to show that atom probe analyses of bulk aqueous specimens come with their own challenges and discuss physical processes that produce the observed phenomena. Our study demonstrates the viability of using frozen water as a carrier for near-atomic-scale analysis of objects in solution by atom probe tomography.

In-vivo efficacy of amodiaquine-artesunate in children with uncomplicated Plasmodium falciparum malaria in western Kenya.

OBJECTIVES: To assess the efficacy of amodiaquine-artesunate in an area with high chloroquine resistance in western Kenya. METHODS: Twenty-eight day in-vivo efficacy trial of amodiaquine-artesunate in 103 children aged 6-59 months in western Kenya with smear-confirmed uncomplicated Plasmodium falciparum malaria. RESULTS: The 28-day uncorrected adequate clinical and parasitological response (ACPR) was 69.0%, with 15.5% Late Clinical Failure and 15.5% Late Parasitologic Failure rates. The PCR-corrected 28-day ACPR was 90.2%. Clinical risk factors for recurrent infection (recrudescences and reinfections) were lower axillary temperature at enrollment and low weight-for-age Z-score. The presence of single nucleotide polymorphisms pfcrt 76T and pfmdr1 86Y at baseline was associated with increased risk of recurrent infections, both reinfections and recrudescences. CONCLUSION: Although artemether-lumefantrine (Coartem) is the first line ACT in Kenya, amodiaquine-artesunate is registered as an option for treatment of uncomplicated P. falciparum and remains an effective alternative to Coartem in western Kenya. Continued amodiaquine monotherapy in the private sector may jeopardize the future use of amodiaquine-artesunate as an alternative artemisinin-based combination therapy.

Dissociation of antitumor potency from anthracycline cardiotoxicity in a doxorubicin analog.

The search for new congeners of the leading anticancer drug doxorubicin has led to an analog that is approximately 1000 times more potent, noncardiotoxic at therapeutic dose levels, and non-cross-resistant with doxorubicin. The new anthracycline, 3'-deamino-3'-(3-cyano-4-morpholinyl)doxorubicin (MRA-CN), is produced by incorporation of the 3' amino group of doxorubicin in a new cyanomorpholinyl ring. The marked increase in potency was observed against human ovarian and breast carcinomas in vitro; it was not accompanied by an increase in cardiotoxicity in fetal mouse heart cultures. Doxorubicin and MRA-CN both produced typical cardiac ultrastructural and biochemical changes, but at equimolar concentrations. In addition, MRA-CN was not cross-resistant with doxorubicin in a variant of the human sarcoma cell line MES-SA selected for resistance to doxorubicin. Thus antitumor efficacy was dissociated from both cardiotoxicity and cross-resistance by this modification of anthracycline structure.

Tolerability of gemcitabine and carboplatin doublet therapy in cats with carcinomas.

BACKGROUND: This study was performed to determine the toxicity of gemcitabine-carboplatin doublet therapy in cats with carcinomas. HYPOTHESIS: Gemcitabine and carboplatin are safe in tumor-bearing cats. ANIMALS: Twenty cats with spontaneously occurring carcinomas. METHODS: A cohort of 6 cats received gemcitabine (2 mg/kg IV) on days 1, 8, and 15 and carboplatin (10 mg/kg IV) immediately after gemcitabine on day 1 of a 21-day cycle. A 2nd cohort of 14 cats received carboplatin 4 hours after gemcitabine on day 1 and gemcitabine on day 8 but not day 15. The cycles were repeated every 21 days. RESULTS: Cats in the 1st cohort received a median of 3.75 cycles per animal (range, 1-6). Two cats (33.3%) developed grade 3 or 4 neutropenia, 1 (16.7%) grade 4 thrombocytopenia, and 1 (16.7%) grade 3 gastrointestinal toxicity. Gemcitabine dose reductions and treatment delays occurred in 1 and 4 cats, respectively. Cats in the 2nd cohort received a median of 2 cycles per animal (range, 0.5-10). Two cats (14.3%) had grade 3 or 4 neutropenia and 1 (7.1%) had grade 3 and 4 gastrointestinal toxicity. One cat required gemcitabine dose reduction and 6 had treatment delays. In the 2nd cohort, of 11 cats with measurable tumors, there was 1 complete response (pancreatic carcinoma) and 1 partial response (squamous cell carcinoma, receiving concurrent nonsteroidal anti-inflammatory drugs). CONCLUSIONS AND CLINICAL IMPORTANCE: Gemcitabine-carboplatin combination appears moderately well tolerated in tumor-bearing cats. Minimal patient benefit suggests that alternative schedules or combinations of gemcitabine with other agents should be explored.

Determination of activity concentration of 238U and 232Th series radionuclides in soil using a gamma-ray spectrometer in singles and coincidence modes.

Traditionally, activity concentrations of naturally occurring radioactive materials (NORMs) are measured using a gamma-ray spectrometer with a single detector shielded with lead. In this measurement, a gamma-ray spectrometer comprising an array of four LaBr3:Ce detectors without shielding was used. This spectrometer allowed for measurement in singles and coincidence (gamma-gamma) modes. In addition to using the coincidence method, a novel method of background reduction by using the photon time-of-flight was utilized. Activity concentration of 238U and 232Th series radionuclides in soil reference (IAEA-375) and beach-sand (Bs) were measured in singles and coincidence modes. In coincidence mode, the minimum detectable activities (MDAs) were lower by a factor of 8-36 than for singles mode. Activity concentration of 238U and 232Th series in soil material (IAEA-375) were determined in coincidence mode while it was below MDA in singles mode. The results correlate with the certified values to within the uncertainty although the uncertainties were high because of low statistics.

Radon in groundwater baseline study prior to unconventional shale gas development and hydraulic fracturing in the Karoo Basin (South Africa).

The prospect of unconventional shale gas development in the semi-arid Karoo Basin (South Africa) has created the prerequisite to temporally characterise the natural radioactivity in associated groundwater which is solely depended on for drinking and agriculture purposes. Radon (222Rn) was the primary natural radionuclide of interest in this study; however, supplementary radium (226Ra and 228Ra) in-water measurements were also conducted. A total of 53 aquifers spanning three provinces were studied during three separate measurement campaigns from 2014 to 2016. The Karoo Basin's natural radon-in-water levels can be characterised by a minimum of 1 ±â€¯1 Bq/L (consistent with zero or below LLD), a maximum of 183 ±â€¯18 Bq/L and mean of 41 ±â€¯5 Bq/L. The mean radon-in-water levels for shallow aquifers were systematically higher (55 ±â€¯10 Bq/L) compared to deep (14 ±â€¯3 Bq/L) or mixed aquifers (20 ±â€¯6 Bq/L). Radon-in-water activity concentration fluctuations were predominantly observed from shallow aquifers compared to the generally steady levels of deep aquifers. A collective seasonal mean radon-in-water levels increase from the winter of 2014 (44 ±â€¯8 Bq/L) to winter of 2016 (61 ±â€¯16 Bq/L) was noticed which could be related to the extreme national drought experienced in 2015. Radium-in-water (228Ra and 226Ra) levels ranged from below detection level to a maximum of 0.008 Bq/L (226Ra) and 0.015 Bq/L (228Ra). The 228Ra/226Ra ratio was characterised by a minimum of 0.93, a maximum of 6.5 and a mean value of 3.3 ±â€¯1.3. Developing and improving baseline naturally occurring radionuclide groundwater databases is vital to study potential radiological environmental impacts attributed to industrial processes such as hydraulic fracturing or mining.