Ammonia emissions and performance of backgrounding and finishing beef feedlot cattle fed barley-based diets varying in dietary crude protein concentration and rumen degradability.
Crossbred beef steers (n = 312) were used in an experiment with a completely randomized design during the growing (235 ± 1.6 kg initial BW) and finishing (363 ± 2.7 kg) phase to determine the effects of dietary CP concentration and rumen degradability on NH3-N emissions, growth performance, and carcass traits. Diets were barley based and consisted of 55% silage and 45% concentrate in the backgrounding phase and 9% silage and 91% concentrate in the finishing phase. For each phase, there were 4 dietary treatments (6 pens of 13 cattle per diet): the basal diet with no protein supplementation (12% CP backgrounding and 12.6% CP finishing) or supplemented (14% CP) with urea (UREA), urea and canola meal (UREA+CM), or urea, corn gluten meal, and xylose-treated soybean meal (UREA+CGM+xSBM). Feed intake and BW of cattle were measured at 3-wk intervals. One pen of steers fed the 12 or 12.6% CP and 1 pen fed 1 of the 14% CP diets were housed in 2 isolated pens to quantify NH3-N emissions using the integrated horizontal flux technique with passive NH3 samplers. In the backgrounding phase final BW, ADG, and G:F were less (P < 0.05) in cattle fed the 12% CP and UREA compared with the UREA+CM and UREA+CGM+xSBM diets. Nitrogen-use efficiency of cattle fed UREA+CM and UREA+CGM+xSBM was equal to that of cattle fed 12% CP and averaged 19.8%. In the finishing phase, there was no effect (P > 0.10) of CP supplementation on BW, DMI, ADG, G:F, N-use efficiency, and carcass traits. The NH3-N emissions from December to February during the backgrounding phase ranged from 4.3 to 25.6 g N/(steer•d) and 3.8 to 16.3% of N intake and from April to July during the finishing phase ranged from 9.7 to 76.4 g N/(steer•d) and 4.4 to 26.7% of N intake. Differences in NH3-N emissions between the pens of cattle fed the backgrounding diets with 12 and 14% CP were not detected. For cattle fed the 12.6 and 14% CP finishing diets, NH3-N emissions tended (P ≤ 0.16) to be less for 2 of the 5 periods and averaged 14.4 and 28.1 g N/(steer•d) and 7.7 and 12.7% of N intake, respectively. The NH3-N emitted as a % of N intake averaged 42% less for cattle fed 12.6% compared with 14% CP. Feeding the barley-based concentrate diet to finishing cattle with 12.6% compared with 14% CP diets reduced NH3-N emissions with no effect on performance. Feeding the barley-based forage diet to backgrounding cattle with 12% CP, however, reduced performance compared with growing cattle fed supplementary degradable and undegradable true protein.


Combined monitoring and modeling indicate the most effective agricultural best management practices.
Although water quality problems associated with agricultural nonpoint source (NPS) pollution have prompted the rapid and widespread adoption of a variety of so called "best management practices" (BMPs), there have been few realistic efforts to assess their combined effectiveness in reducing NPS pollution. This study used the Variable Source Loading Function (VSLF) model, a distributed watershed model, to simulate phosphorus (P) loading from an upstate New York dairy farm before and after the implementation of a suite of BMPs. With minimal calibration, the model calculates the dissolved P (DP) losses from impervious surfaces (e.g., barnyards), the plant/soil complex, field-applied manure, and loads associated with baseflow conditions. The simulated DP loads agreed well with measured loads for both the pre-BMP and post-BMP periods. More importantly, results showed that BMPs reduced DP loads by 35%, which is over half of the expected reduction if all manure was removed from the watershed, i.e., approximately 50% reduction. The model results indicate that had no BMPs been installed DP loads would be approximately 37% greater than observed at the watershed outlet. The most effective BMPs were those that disassociated pollutant loading areas from areas prone to generating runoff, i.e., hydrologically sensitive areas. By contrast, attempts to reduce P content in manure were somewhat less effective. This study demonstrates that a combination of distributed, mechanistic modeling and long-term monitoring provides better insights into the effectiveness of water quality protection efforts than either individually.


Unilateral thyrovertebral trunk: report of a rare arterial variant.
Atypical origins of the vertebral and the inferior thyroid arteries are rare anatomical findings. We present the case of a right-sided thyrovertebral trunk observed in a 91-year-old female cadaver. In this extremely rare vascular variation both the vertebral and the inferior thyroid arteries jointly originated from the subclavian artery as its first branch by forming a short trunk. A thyrocervical trunk was absent resulting in anomalous origins of most subclavian branches. The vertebral artery travelled cranially entering the transverse foramen of the fifth cervical vertebrae. We furthermore discuss the clinical significance of this variation in the context of surgical and interventional procedures performed in the lateral neck region.


Reststrahlen band studies of polycrystalline beryllium oxide.
New experimental bulk reflectance and emittance spectra from the 9-15-µm reststrahlen band region of polycrystallline beryllium oxide are reported. Note that the polycrystalline material exhibits a dip at 10 pm, which is not present in spectra for single crystals. The possible origins of this feature are discussed including absorption by a surfaceboscillation excited at boundaries of 20-µm crystalline grains. Owing to the reststrahlen band, beryllium oxide is selectively low, emitting in the primary atmospheric window, which makes this material useful for frost prevention when electrical conductors cannot be used. This protection is susceptible to reduction by surface contaminants from air pollution. Using an established acceleration procedure, we simulated such pollution, and the increase in emittance was measured. It was observed that the emissivity increased from 0.31 for a clean surface to 0.36 for a surface heavily polluted by an industrial atmosphere.


A preliminary randomized controlled trial of contingency management for alcohol use reduction using a transdermal alcohol sensor.
We tested the efficacy of daily contingent reinforcement for reducing alcohol use compared with (yoked) non-contingent reinforcement (NR) using a transdermal alcohol sensor to detect alcohol use. Pilot randomized controlled design with 1 baseline week, 3 intervention weeks and 1-month follow-up. New England, USA. Heavy drinking adults (46.7% female) not seeking treatment were randomized to (1) an escalating schedule of cash reinforcement (CR; n = 15) for days on which alcohol was neither reported nor detected or (2) yoked NR (n = 15). Reinforcement for CR participants started at $5 and increased $2 every subsequent day on which alcohol was not detected or reported, to a maximum of $17. Participants received no reinforcement for days on which alcohol use was detected or reported, and the reinforcer value was re-set to $5 the day after a drinking day. NR participants were yoked to the daily reinforcer value of an individual in the CR condition, in order of enrollment. Paired participants in CR and NR therefore received the same amount of money, but the amount for the NR participant was not behavior-related. The primary outcome was percentage of days without sensor-detected drinking. Secondary outcomes were number of consecutive days with no detected drinking, peak transdermal alcohol concentration (TAC), self-reported drinks per week and drinking below NIH low-risk guidelines. Controlling for baseline, CR had a higher percentage of days with no drinking detected (54.3%) than NR (31.2%) during intervention weeks [P = 0.05, Cohen's d = 0.74; 95% confidence interval (CI) = 0.007-1.47]. The longest period of consecutive days with no drinking detected was 8.0 for CR versus 2.9 for NR (P = 0.03, d = 0.85; 95% CI = 0.08-1.61). Peak TAC during intervention showed a non-significant group difference (P = 0.20; d = 0.48; 95% CI = 0.00-1.18); a similar result was found for drinks per week (P = 0.12; d = 0.59; 95% CI = 0.00-1.30). Four times more participants in CR drank below NIH low-risk drinking guidelines during intervention than did participants in NR: 31.1 versus 7.1% (P = 0.07; d = 0.71; 95% CI = -0.04 to 1.46). At 1-month follow-up, the highest number of consecutive days without drinking (self-report) did not differ significantly between conditions (P = 0.26), but showed a medium effect size (d = 0.44; 95% CI = -0.32 to 1.18). Cash incentives linked to a transdermal alcohol sensor can reduce heavy alcohol consumption while the incentives are in operation.


Factors associated with body function and disability in patients with ankylosing spondylitis: a cross-sectional study.
To determine for patients with ankylosing spondylitis (AS) which factors are associated with disability and restricted body function. In 1538 patients with AS, occiput-to-wall distance, chest expansion, cervical rotation, finger-floor distance, and modified Schober test were measured cross-sectionally, and for each measure the patient's respective percentile was calculated. The mean of the 5 percentiles was summarized in the mobility restriction score (MRS). In addition, patients answered questions on disease progression and completed the Bath AS Functional Index (BASFI) questionnaire. All data were coded into 40 variables, used as independent variables in multiple regression analyses to identify factors associated with BASFI and MRS. Finger-to-floor distance (beta positive, +), cervical rotation (-), time since first AS symptoms (-), age (+), height loss (+), maximum height (-), delay in diagnosis (+), hip replacement (+), regular practice of sports (-), chest expansion (-), sex (worse BASFI in females), exposure to cold and dampness (+), and regular participation in AS group physical exercises (+) were significantly associated with worse BASFI. Significantly associated factors for worse MRS were height loss (+), sex (higher MRS in males), active inflammation of the cervical region (+), age (+), maximum height (-), active inflammation of the hip region (+), involvement of shoulders (+), time since first AS symptoms (+), urethritis (-), regular practice of sports (-), involvement of feet (-), and hip replacement (+). The models explain 47% of the variance observed for both the BASFI and MRS. The amount of variance explained for both BASFI and MRS is rather high. The results apply primarily to groups of patients, but are insufficient to guide clinical decisions in individual patients. These findings contribute to our understanding of factors influencing disability and restriction in body function in AS.


Towards Phenotyping of Clinical Trial Eligibility Criteria.
Medical plaintext documents contain important facts about patients, but they are rarely available for structured queries. The provision of structured information from natural language texts in addition to the existing structured data can significantly speed up the search for fulfilled inclusion criteria and thus improve the recruitment rate. This work is aimed at supporting clinical trial recruitment with text mining techniques to identify suitable subjects in hospitals. Based on the inclusion/exclusion criteria of 5 sample studies and a text corpus consisting of 212 doctor's letters and medical follow-up documentation from a university cancer center, a prototype was developed and technically evaluated using NLP procedures (UIMA) for the extraction of facts from medical free texts. It was found that although the extracted entities are not always correct (precision between 23% and 96%), they provide a decisive indication as to which patient file should be read preferentially. The prototype presented here demonstrates the technical feasibility. In order to find available, lucrative phenotypes, an in-depth evaluation is required.


Potential role of specific antibodies as important vaccine induced protective mechanism against Aeromonas salmonicida in rainbow trout.
Furunculosis caused by infection with Aeromonas salmonicida subsp. salmonicida has been a known threat to aquaculture for more than a century. Efficient prophylactic approaches against this disease are essential for continued growth of salmonid aquaculture. Since the introduction of successful oil-adjuvanted vaccines in the early 1990's, a number of studies have been published on the protective as well as adverse effects of these vaccines. Most studies focus on vaccination of salmon (Salmo salar). However, rainbow trout (Oncorhynchus mykiss) are also very susceptible to infection and are vaccinated accordingly. In this study we have examined the protection against infection with a Danish strain of A. salmonicida in both vaccinated and non-vaccinated rainbow trout. A commercial and an experimental auto-vaccine were tested. The protective effects of the vaccines were evaluated through an A. salmonicida challenge 18 weeks post vaccination. Both vaccines resulted in a significantly increased survival in the vaccinated fish during a 28 day challenge period relative to non-vaccinated fish (P = 0.01 and P = 0.001 for the commercial and experimental vaccine, respectively). Throughout the entire experiment, the presence of specific antibodies in plasma was monitored using ELISA. A significant increase in specific antibody levels was seen in fish vaccinated with both vaccines during the 18 weeks between vaccination and challenge. Within 3 days post challenge, a significant decrease in specific antibodies occurred in vaccinated fish. A positive correlation was found between mean levels of specific antibodies pre challenge and overall survival. This correlation, along with the observed depletion of antibodies during the initial phase of infection, suggests that specific antibodies play an essential role in vaccine mediated protection against A. salmonicida in rainbow trout.


Hollow carbon nanofiber-encapsulated sulfur cathodes for high specific capacity rechargeable lithium batteries.
Sulfur has a high specific capacity of 1673 mAh/g as lithium battery cathodes, but its rapid capacity fading due to polysulfides dissolution presents a significant challenge for practical applications. Here we report a hollow carbon nanofiber-encapsulated sulfur cathode for effective trapping of polysulfides and demonstrate experimentally high specific capacity and excellent electrochemical cycling of the cells. The hollow carbon nanofiber arrays were fabricated using anodic aluminum oxide (AAO) templates, through thermal carbonization of polystyrene. The AAO template also facilitates sulfur infusion into the hollow fibers and prevents sulfur from coating onto the exterior carbon wall. The high aspect ratio of the carbon nanofibers provides an ideal structure for trapping polysulfides, and the thin carbon wall allows rapid transport of lithium ions. The small dimension of these nanofibers provides a large surface area per unit mass for Li(2)S deposition during cycling and reduces pulverization of electrode materials due to volumetric expansion. A high specific capacity of about 730 mAh/g was observed at C/5 rate after 150 cycles of charge/discharge. The introduction of LiNO(3) additive to the electrolyte was shown to improve the Coulombic efficiency to over 99% at C/5. The results show that the hollow carbon nanofiber-encapsulated sulfur structure could be a promising cathode design for rechargeable Li/S batteries with high specific energy.


Prenatal exposure to diclofenac sodium changes the morphology of the male rat cervical spinal cord: a stereological and histopathological study.
Diclofenac sodium is one of the most commonly used non-steroidal anti-inflammatory drugs. It may cause alteration in the nervous system during neuronal development. However, there is no investigation concerning its role in the cervical spinal cord. Pregnant rats were divided into two groups, namely drug-treated and control (saline-injected) groups. To obtain the offspring of the drug-treated group, a dose of 1mg/kg daily diclofenac sodium (Voltaren, 75 mg/3 ml ampoule, Novartis) was injected into the pregnant rats beginning from the 5th day after mating to the 20th day of the pregnancy. To obtain the control group of offspring, serum physiological at a 1 ml/kg daily dose was injected into the pregnant control rats during the same period. Male offspring were obtained after delivery and each group was divided into two subgroups: 4-week-old and 20-week-old. The total neuron number in diclofenac sodium-treated rats was significantly lower than in the control group animals. The total volume of the cervical spinal cord segments (C1-C4) was also estimated. There was a significant difference between the volumes of the two groups, especially in the 20-week-old subgroup. This may suggest that development of neurons and volume of cervical spinal cord are affected in prenatal animals after administration of diclofenac sodium.


No One Dies Alone: Addressing a Gap in Medical Education.
Medical school curriculum typically consists of didactical experiences with minimal patient interaction for junior students followed by clinical experiences with supplementary didactics for senior students. Due to the focus on understanding basic medical concepts and disease pathophysiology during the first few years of medical school, students have limited exposure to real-life clinical situations that involve complex, difficult concepts such as death and dying. This leaves students ill-prepared to contribute meaningfully to patients' end-of-life (EOL) care that they will inevitably encounter during their clerkship years. We believe that students would benefit from increased exposure to these difficult situations through structured educational environments, such as the No One Dies Alone Program. In this way, students can become more familiar with the difficult concepts of death and dying, learn how to make meaningful contributions in their patients' EOL care, and ultimately provide patients with the "good death" they deserve.


An atypical presentation of sinus mucopyocele in a pediatric cystic fibrosis patient.
This case report details an association of chronic allergic conjunctivitis and respiratory tract colonization in a cystic fibrosis (CF) patient due to an ethmoidal mucocele infected with Escherichia coli. A 3-year-old CF patient presented for evaluation with complaints of chronic periocular erythema, conjunctival injection, and irritation for 2 years. He was treated for presumed allergic conjunctivitis with no improvement and continued to have overall worsening of symptoms on the right greater than the left eye in a waxing and waning pattern. On presentation to the Bascom Palmer Eye Institute, he was noted to have telecanthus and prominent erythema in the region of the medial canthus. Orbital imaging disclosed a mucocele in the right ethmoid sinus. The patient underwent functional endoscopic sinus surgery, with successful marsupialization of the ethmoidal mucocele, which was found on culture to be infected with E. coli. Post-operatively with continuous pulmonary care, the patient remains free of allergic conjunctivitis and E. coli colonization of the upper airway. This case highlights the importance of analyzing the adjacent sinus in patients with chronic, relapsing allergic conjunctivitis refractory to medical management, particularly in patients with underlying systemic diseases such as CF.


Molecular Insights into Covalently Stained Carious Dentine Using Solid-State NMR and ToF-SIMS.
Dyes currently used to stain carious dentine have a limited capacity to discriminate normal dentine from carious dentine, which may result in overexcavation. Consequently, finding a selective dye is still a challenge. However, there is evidence that hydrazine-based dyes, via covalent bonds to functional groups, bind specifically to carious dentine. The aim of this study was to investigate the possible formation of covalent bonds between carious dentine and 15N2-hydrazine and the hydrazine-based dye, 15N2-labelled Lucifer Yellow, respectively. Powdered dentine from extracted carious and normal teeth was exposed to the dyes, and the staining reactions were analysed using time-of-flight secondary ion mass spectrometry (ToF-SIMS), solid-state 13C-labelled nuclear magnetic resonance (NMR) and 15N-NMR spectroscopy. The results showed that 15N2-hydrazine and 15N2-labelled Lucifer Yellow both bind to carious dentine but not to normal dentine. It can thus be concluded that hydrazine-based dyes can be used to stain carious dentine and leave normal dentine unstained.


Drosophila maternal and embryo mRNAs transcribed from a single transcription unit use alternate combinations of exons.
We have investigated the organization and transcription of several genes in Drosophila melanogaster which are clustered on an 18-kb cloned DNA fragment (c25) that maps at 99D on the cytogenetic map. Multiple mRNAs, transcribed from genes which lie adjacent to a ribosomal protein ( rp49 ) gene, are present during oogenesis, embryogenesis, or both. At least five mRNAs are transcribed from one of these genes ( EH8 ); three are zygotic transcripts, of which two are blastoderm stage-specific, whereas two others accumulate during oogenesis and are therefore matenal mRNAs. The complex transcription pattern of this gene indicates that alternate usage of protein-coding exons results in the production of different mRNAs with different coding capabilities during oogenesis and embryogenesis. The EH8 transcription unit is framed by genes actively expressed in the adult male fly; thus, the blastoderm stage-specific promoter may be silent although within a region of transcriptionally active chromatin.


E6AP promotes prostate cancer by reducing p27 expression.
Prostate cancer (PC) is the most common cancer in men. Elevated levels of E3 ligase, E6-Associated Protein (E6AP) were previously linked to PC, consistent with increased protein expression in a subset of PC patients. In cancers, irregular E3 ligase activity drives proteasomal degradation of tumor suppressor proteins. Accordingly, E3 ligase inhibitors define a rational therapy to restore tumor suppression. The relevant tumor suppressors targeted by E6AP in PC are yet to be fully identified. In this study we show that p27, a key cell cycle regulator, is a target of E6AP in PC. Down regulation of E6AP increases p27 expression and enhances its nuclear accumulation in PC. We demonstrate that E6AP regulates p27 expression by inhibiting its transcription in an E2F1-dependent manner. Concomitant knockdown of E6AP and p27 partially restores PC cell growth, supporting the contribution of p27 to the overall effect of E6AP on prostate tumorigenesis. Overall, we unravelled the E6AP-p27 axis as a new promoter of PC, exposing an attractive target for therapy through the restoration of tumor suppression.


Identification of Putative Genes Involved in Bisphenol A Degradation Using Differential Protein Abundance Analysis of Sphingobium sp. BiD32.
Discharge of the endocrine disrupting compound bisphenol A (BPA) with wastewater treatment plant (WWTP) effluents into surface waters results in deleterious effects on aquatic life. Sphingobium sp. BiD32 was previously isolated from activated sludge based on its ability to degrade BPA. This study investigated BPA metabolism by Sphingobium sp. BiD32 using label-free quantitative proteomics. The genome of Sphingobium sp. BiD32 was sequenced to provide a species-specific platform for optimal protein identification. The bacterial proteomes of Sphingobium sp. BiD32 in the presence and absence of BPA were identified and quantified. A total of 2155 proteins were identified; 1174 of these proteins were quantified, and 184 of these proteins had a statistically significant change in abundance in response to the presence/absence of BPA (p ≤ 0.05). Proteins encoded by genes previously identified to be responsible for protocatechuate degradation were upregulated in the presence of BPA. The analysis of the metabolites from BPA degradation by Sphingobium sp. BiD32 detected a hydroxylated metabolite. A novel p-hydroxybenzoate hydroxylase enzyme detected by proteomics was implicated in the metabolic pathway associated with the detected metabolite. This enzyme is hypothesized to be involved in BPA degradation by Sphingobium sp. BiD32, and may serve as a future genetic marker for BPA degradation.


Analysis of CD10+ hairy cell leukemia.
Hairy cell leukemia (HCL) has been reported to sometimes express CD10. However, the reported frequencies have been quite variable and the significance of CD10 expression has not been addressed. Cases of HCL submitted to our flow cytometry service during a 2-year period were evaluated for CD10 expression. Information regarding demographics, clinical manifestations, tissue morphologic features, and response to treatment was reviewed. Of the 97 HCL cases identified, 10 expressed CD10. The level of CD10 staining was typically well above control levels and also could be detected easily by immunohistochemical analysis. All cases analyzed were negative for bcl-6. Our study suggests that approximately 10% of otherwise typical cases of HCL show aberrant CD10 expression. CD10+ HCL cases seem to be morphologically and clinically similar to CD10-HCL cases. Appreciating that HCL can express CD10 may be especially important when evaluating specimens with suboptimal morphologic features and/or limited immunophenotyping panels.


Influences of surface coating of PLGA nanoparticles on immune activation of macrophages.
Poly(lactide-co-glycolide) (PLGA) is one of the most attractive biodegradable polymers for loading and delivering payloads, especially in the form of nanoparticles (NPs). In this work, NPs of PLGA with 3 different molecular weights were fabricated using bovine serum albumin (BSA) and polyethyleneimine (PEI) as dispersing agents. Elemental analysis revealed that the loading amounts of BSA and PEI were 40-60 μg mg-1 and 12-15 μg mg-1 in the BSA/PLGA NPs and PEI/PLGA NPs, respectively. About 13-18 μg mg-1 BSA was exposed onto the surface of the BSA/PLGA NPs. No degradation of the PLGA NPs was detected after being incubated in artificial lysosomal fluid or with macrophages in a culture medium for 7 days. The innate immune activation behavior of the BSA/PLGA and PEI/PLGA NPs was evaluated by co-incubation with RAW264.7 cells in vitro. PLGA NPs fabricated with different molecular weights of PLGA showed no difference in stimulating RAW264.7 cells. The PEI/PLGA NPs did not show significant immune activation in terms of secretion of inflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) too. By contrast, the BSA/PLGA NPs induced a significantly higher expression of TNF-α, likely due to the heterogeneous albumin and existence of endotoxin, and the synergistic role of larger uptake of the BSA/PLGA NPs by macrophages.


Measurement of Hybrid III Head Impact Kinematics Using an Accelerometer and Gyroscope System in Ice Hockey Helmets.
Helmet-based instrumentation is used to study the biomechanics of concussion. The most extensively used systems estimate rotational acceleration from linear acceleration, but new instrumentation measures rotational velocity using gyroscopes, potentially reducing error. This study compared kinematics from an accelerometer and gyroscope-containing system to reference measures. A Hybrid III (HIII) adult male anthropometric test device head and neck was fit with two helmet brands, each instrumented with gForce Tracker (GFT) sensor systems in four locations. Helmets were impacted at various speeds and directions. Regression relationships between GFT-measured and reference peak kinematics were quantified, and influence of impact direction, sensor location, and helmet brand was evaluated. The relationship between the sensor output and the reference acceleration/velocity experienced by the head was strong. Coefficients of determination for data stratified by individual impact directions ranged from 0.77 to 0.99 for peak linear acceleration and from 0.78 to 1.0 for peak rotational velocity. For the data from all impact directions combined, coefficients of determination ranged from 0.60 to 0.80 for peak resultant linear acceleration and 0.83 to 0.91 for peak resultant rotational velocity. As expected, raw peak resultant linear acceleration measures exhibited large percent differences from reference measures. Adjustment using regressions resulted in average absolute errors of 10-15% if regression adjustments were done by impact direction or 25-40% if regressions incorporating data from all impact directions were used. Average absolute percent differences in raw peak resultant rotational velocity were much lower, around 10-15%. It is important to define system accuracy for a particular helmet brand, sensor location, and impact direction in order to interpret real-world data.


Genomewide linkage scan for diabetic renal failure and albuminuria: the FIND study.
Diabetic nephropathy (DN) is a leading cause of mortality and morbidity in patients with type 1 and type 2 diabetes. The multicenter FIND consortium aims to identify genes for DN and its associated quantitative traits, e.g. the urine albumin:creatinine ratio (ACR). Herein, the results of whole-genome linkage analysis and a sparse association scan for ACR and a dichotomous DN phenotype are reported in diabetic individuals. A genomewide scan comprising more than 5,500 autosomal single nucleotide polymorphism markers (average spacing of 0.6 cM) was performed on 1,235 nuclear and extended pedigrees (3,972 diabetic participants) ascertained for DN from African-American (AA), American-Indian (AI), European-American (EA) and Mexican-American (MA) populations. Strong evidence for linkage to DN was detected on chromosome 6p (p = 8.0 × 10(-5), LOD = 3.09) in EA families as well as suggestive evidence for linkage to chromosome 7p in AI families. Regions on chromosomes 3p in AA, 7q in EA, 16q in AA and 22q in MA displayed suggestive evidence of linkage for urine ACR. The linkage peak on chromosome 22q overlaps the MYH9/APOL1 gene region, previously implicated in AA diabetic and nondiabetic nephropathies. These results strengthen the evidence for previously identified genomic regions and implicate several novel loci potentially involved in the pathogenesis of DN.


Effects of Organic Acid Anions on the Growth and Metabolism of Syntrophomonas wolfei in Pure Culture and in Defined Consortia.
The effects of organic acid anions on the growth of Syntrophomonas wolfei was determined by varying the initial concentration of the acid anion in the medium. The addition of 15 mM acetate decreased the growth rate of a butyrate-catabolizing coculture containing Methanospirillum hungatei from 0.0085 to 0.0029 per hour. Higher initial acetate concentrations decreased the butyrate degradation rate and the yield of cells of S. wolfei per butyrate degraded. Inhibition was not due to the counter ion or the effect of acetate on the methanogen. Initial acetate concentrations above 25 mM inhibited crotonate-using pure cultures and cocultures of S. wolfei. Benzoate and lactate inhibited the growth of S. wolfei on crotonate in pure culture and coculture. Lactate was an effective inhibitor of S. wolfei cultures at concentrations greater than 10 mM. High concentrations of acetate and lactate altered the electron flow in crotonate-catabolizing cocultures, resulting in the formation of less methane and more butyrate and caproate. The inclusion of the acetate-using methanogen, Methanosarcina barkeri, in a methanogenic butyrate-catabolizing coculture increased both the yield of S. wolfei cells per butyrate degraded and the efficacy of butyrate degradation. Butyrate degradation by acetate-inhibited cocultures occurred only after the addition of Methanosarcina barkeri. These results showed that the metabolism of S. wolfei was inhibited by high levels of organic acid anions. The activity of acetate-using methanogens is important for the syntrophic degradation of fatty acids when high levels of acetate are present.


Assessment of bone healing using (Ti,Mg)N thin film coated plates and screws: Rabbit femur model.
Magnesium (Mg) based implants such as plates and screws are often preferred to treat bone defects because of the positive effects of magnesium in bone growth and healing. Their low corrosion resistance, however, leads to fast degradation and consequently failure before healing was completed. Previously, we developed Mg doped titanium nitrate (TiN) thin film coatings to address these limitations and demonstrated that <10 at% Mg doping led to enhanced mineralization in vitro. In the present study, in vivo performance of (Ti,Mg)N coated Ti6Al4V based plates and screws were studied in the rabbit model. Bone fractures were formed on femurs of 16 rabbits and then fixed with either (Ti,Mg)N coated (n = 8) or standard TiN coated (n = 8) plates and screws. X-ray imaging and μCT analyses showed enhanced bone regeneration on fracture sites fixed with (Ti,Mg)N coated plates in comparison with the Mg free ones. Bone mineral density, bone volume, and callus volume were also found to be 11.4, 23.4, and 42.8% higher, respectively, in accordance with μCT results. Furthermore, while TiN coatings promoted only primary bone regeneration, (Ti,Mg)N led to secondary bone regeneration in 6 weeks. These results indicated that Mg presence in the coatings accelerated bone regeneration in the fracture site. (Ti,Mg)N coating can be used as a practical method to increase the efficiency of existing bone fixation devices of varying geometry.


Breaking silence: a survey of barriers to goals of care discussions from the perspective of oncology practitioners.
Cancer is the leading cause of death in the developed world, and yet healthcare practitioners infrequently discuss goals of care (GoC) with hospitalized cancer patients. We sought to identify barriers to GoC discussions from the perspectives of staff oncologists, oncology residents, and oncology nurses. This was a single center survey of staff oncologists, oncology residents, and inpatient oncology nurses. Barriers to GoC discussions were assessed on a 7-point Likert scale (1 = extremely unimportant; 7 = extremely important). Between July 2013 and May 2014, of 185 eligible oncology clinicians, 30 staff oncologists, 10 oncology residents, and 28 oncology nurses returned surveys (response rate of 37%). The most important barriers to GoC discussions were patient and family factors. They included family members' difficulty accepting poor prognoses (mean score 5.9, 95% CI [5.7, 6.2]), lack of family agreement in the goals of care (mean score 5.8, 95% CI [5.5, 6.1]), difficulty understanding the limitations of life-sustaining treatments (mean score 5.8, 95% CI [5.6, 6.1]), lack of patients' capacity to make goals of care decisions (mean score 5.7, 95% CI [5.5, 6.0]), and language barriers (mean score 5.7, 95% CI [5.4, 5.9]). Participants viewed system factors and healthcare provider factors as less important barriers. Oncology practitioners perceive patient and family factors as the most limiting barriers to GoC discussions. Our findings underscore the need for oncology clinicians to be equipped with strong communication skills to help patients and families navigate GoC discussions.


Elimination of hepatitis C virus infection among people who use drugs: Ensuring equitable access to prevention, treatment, and care for all.
There have been major strides towards the World Health Organization goal to eliminate hepatitis C virus (HCV) infection as a global public health threat. The availability of simple, well-tolerated direct-acting antiviral therapies for HCV infection that can achieve a cure in >95% of people has provided an important tool to help achieve the global elimination targets. Encouragingly, therapy is highly effective among people receiving opioid agonist therapy and people who have recently injected drugs. Moving forward, major challenges include ensuring that new infections are prevented from occurring and that people who are living with HCV are tested, linked to care, treated, receive appropriate follow-up, and have equitable access to care. This editorial highlights key themes and articles in a special issue focusing on the elimination of HCV among people who inject drugs. An overarching consideration flowing from this work is how to ensure equitable access to HCV treatment and care for all. This special issue maps the field in relation to: HCV prevention; the cascade of HCV care; strategies to enhance testing, linkage to care, and treatment uptake; and HCV treatment and reinfection. In addition, papers draw attention to the 'risk environments' and socio-ecological determinants of HCV acquisition, barriers to HCV care, the importance of messaging around the side-effects of new direct-acting antiviral therapies, the positive transformative potential of treatment and cure, and the key role of community-based drug user organizations in the HCV response. While this special issue highlights some successful efforts towards HCV elimination among people who inject drugs, it also highlights the relative lack of attention to settings in which resources enabling elimination are scarce, and where elimination hopes and potentials are less clear, such as in many low and middle income countries. Strengthening capacity in areas of the world where resources are more limited will be a critical step towards ensuring equity for all so that global HCV elimination among PWID can be achieved.


Rapid detection of Peste des Petits Ruminants (PPR) virus antigen in Sudan by agar gel precipitation (AGPT) and haemagglutination (HA) tests.
AGPT and HA tests were employed for rapid diagnosis of PPRV infection in sheep and goats in Sudan. Forty lymph nodes and spleen samples from suspected cases of PPR in both sheep and goats were examined by AGPT and HA tests for detection of PPRV antigen. Viral antigen was detected from (77.5%) of the samples tested by AGPT and (92.5%) tested by HA test. The results of both tests revealed that HA test was more sensitive than AGPT for detection of PPRV antigen (Kappa statistics 0.4366). Another advantage of the HA test over AGPT was that it can differentiate PPRV from RPV. Thus the HA test represents a quick, easy, simple, cheap and reliable confirmatory test for the diagnosis of PPR and differential diagnosis of PPRV and RPV. The HA test was carried out using chicken, goat and pig RBCs. Chicken RBCs were found to be the most sensitive for detection of PPRV antigen, followed by goat then pig RBCs. The HA time when using chicken RBCs was 20-25 minutes, using goat RBCs was 25-30 minutes and using pig RBCs was 40-45 minutes. The distribution of PPR infection in four different regions of Sudan was investigated.


The Frequency of Vaccine-Induced T-Cell Responses Does Not Predict the Rate of Acquisition after Repeated Intrarectal SIVmac239 Challenges in Mamu-B*08+ Rhesus Macaques.
Approximately 50% of rhesus macaques (RMs) expressing the major histocompatibility complex class I (MHC-I) allele Mamu-B*08 spontaneously control chronic-phase viremia after infection with the pathogenic simian immunodeficiency virus mac239 (SIVmac239) clone. CD8+ T-cell responses in these animals are focused on immunodominant Mamu-B*08-restricted SIV epitopes in Vif and Nef, and prophylactic vaccination with these epitopes increases the incidence of elite control in SIVmac239-infected Mamu-B*08-positive (Mamu-B*08+ ) RMs. Here we evaluated if robust vaccine-elicited CD8+ T-cell responses against Vif and Nef can prevent systemic infection in Mamu-B*08+ RMs following mucosal SIV challenges. Ten Mamu-B*08+ RMs were vaccinated with a heterologous prime/boost/boost regimen encoding Vif and Nef, while six sham-vaccinated MHC-I-matched RMs served as the controls for this experiment. Vaccine-induced CD8+ T cells against Mamu-B*08-restricted SIV epitopes reached high frequencies in blood but were present at lower levels in lymph node and gut biopsy specimens. Following repeated intrarectal challenges with SIVmac239, all control RMs became infected by the sixth SIV exposure. By comparison, four vaccinees were still uninfected after six challenges, and three of them remained aviremic after 3 or 4 additional challenges. The rate of SIV acquisition in the vaccinees was numerically lower (albeit not statistically significantly) than that in the controls. However, peak viremia was significantly reduced in infected vaccinees compared to control animals. We found no T-cell markers that distinguished vaccinees that acquired SIV infection from those that did not. Additional studies will be needed to validate these findings and determine if cellular immunity can be harnessed to prevent the establishment of productive immunodeficiency virus infection.IMPORTANCE It is generally accepted that the antiviral effects of vaccine-induced classical CD8+ T-cell responses against human immunodeficiency virus (HIV) are limited to partial reductions in viremia after the establishment of productive infection. Here we show that rhesus macaques (RMs) vaccinated with Vif and Nef acquired simian immunodeficiency virus (SIV) infection at a lower (albeit not statistically significant) rate than control RMs following repeated intrarectal challenges with a pathogenic SIV clone. All animals in the present experiment expressed the elite control-associated major histocompatibility complex class I (MHC-I) molecule Mamu-B*08 that binds immunodominant epitopes in Vif and Nef. Though preliminary, these results provide tantalizing evidence that the protective efficacy of vaccine-elicited CD8+ T cells may be greater than previously thought. Future studies should examine if vaccine-induced cellular immunity can prevent systemic viral replication in RMs that do not express MHC-I alleles associated with elite control of SIV infection.


Immunohistochemical and functional correlations of renal cyclooxygenase-2 in experimental diabetes.
Prostaglandins (PGs) generated by the enzyme cyclooxygenase (COX) have been implicated in the pathological renal hemodynamics and structural alterations in diabetes mellitus, but the role of individual COX isoenzymes in diabetic nephropathy remains unknown. We explored COX-1 and COX-2 expression and hemodynamic responses to the COX-1 inhibitor valeryl salicylate (VS) or the COX-2 inhibitor NS398 in moderately hyperglycemic, streptozotocin-diabetic (D) and control (C) rats. Immunoreactive COX-2 was increased in D rats compared with C rats and normalized by improved glycemic control. Acute systemic administration of NS398 induced no significant changes in mean arterial pressure and renal plasma flow in either C or D rats but reduced glomerular filtration rate in D rats, resulting in a decrease in filtration fraction. VS had no effect on renal hemodynamics in D rats. Both inhibitors decreased urinary excretion of PGE(2). However, only NS398 reduced excretion of thromboxane A(2). In conclusion, we documented an increase in renal cortical COX-2 protein expression associated with a different renal hemodynamic response to selective systemic COX-2 inhibition in D as compared with C animals, indicating a role of COX-2-derived PG in pathological renal hemodynamic changes in diabetes.


Coiling and clipping of middle cerebral artery aneurysms: a systematic review on clinical and imaging outcome.
There is an ongoing debate on the preferred treatment of middle cerebral artery (MCA) aneurysms. The purpose of this study was to assess the clinical and imaging outcomes comparing conventional coiling and clipping of unruptured and ruptured MCA aneurysms. We searched the electronic databases PubMed, EMBASE, and Cochrane from January 1990 to May 2014. 51 studies were included in the analysis. Favorable outcome was reported in 97.0% and 77.1%, and in 97.2% and 72.8% of patients after coiling and clipping of unruptured and ruptured aneurysms, respectively. Death rates were 1.1% and 8.4% after coiling and 0.3% and 14.7% after clipping of unruptured and ruptured aneurysms, respectively. Initial adequate occlusion was obtained in 89.6% and 92.1% after coiling of unruptured and ruptured aneurysms, respectively. Only three studies on clipping reported on aneurysm occlusion during follow-up. Both coiling and clipping are procedures with low mortality and morbidity rates and, although it may seem that coiling is better for ruptured aneurysms and clipping for unruptured aneurysms, no firm conclusions can be drawn due to the variation in study design and lack of standardized reporting on MCA aneurysm treatments. Standardized observational studies from prospectively kept databases are needed to allow stronger conclusions to be drawn on what is the best treatment for MCA aneurysms. Comparable with aneurysms in other locations, a multidisciplinary approach is therefore recommended with selection of treatment modality based on the clinical condition of the patient and the morphological aspects of the aneurysm.


Effects of distillers dried grains with solubles on amino acid, energy, and fiber digestibility and on hindgut fermentation of dietary fiber in a corn-soybean meal diet fed to growing pigs.
The objective of this experiment was to measure the effect of distillers dried grains with solubles (DDGS) on the digestibility of AA, energy, and fiber, on the fermentation of fiber, and on the first appearance of digesta at the end of the ileum, in the cecum, and in the feces of growing pigs fed a corn-soybean meal-based diet. Sixteen pigs (initial BW = 38.0 +/- 1.6 kg) were prepared with a T-cannula in the distal ileum and a T-cannula in the cecum and allotted to 2 treatments. In period 1, all pigs were fed a corn-soybean meal diet. In periods 2, 3, and 4, pigs were fed the control diet or a diet containing corn, soybean meal, and 30% DDGS. First appearance of digesta at the end of the ileum, in the cecum, and over the entire intestinal tract was measured at the end of period 4. The apparent ileal digestibility (AID) and the apparent total tract digestibility (ATTD) of nutrients were measured, and the concentration of VFA was analyzed in ileal, cecal, and fecal samples. The AID of Lys (74.1%) in the DDGS diet was less (P < 0.05) than in the control diet (78.6%), but the AID of most other AA and GE, NDF, and total dietary fiber (TDF) were not different between the 2 diets. The ATTD of GE (81.0%), NDF (57.2%), TDF (55.5%), and DM (81.7%) were less (P < 0.05) in the DDGS diet than in the control diet (86.0, 69.3, 66.0, and 87.2%, respectively). The concentration of VFA in ileal, cecal, and fecal samples was not different between pigs fed the 2 diets. The pH of ileal and cecal digesta from pigs fed the DDGS diet (6.3 and 5.5) was greater (P < 0.01) than from pigs fed the control diet (5.8 and 5.3). The ATTD of DM, GE, ADF, NDF, and TDF did not change with collection period, but the AID of ADF, NDF, and TDF increased (P < 0.05) from period 2 to period 4. The concentration of all VFA, except isobutyrate, was greater (P < 0.05) in cecal samples from period 4 compared with period 2, and the concentration of all VFA except propionate and isovalerate were greater (P < 0.05) in fecal samples collected in period 4 compared with those collected in period 2. The first appearance of digesta at the end of the ileum, in the cecum, and in the feces was not affected by DDGS. In conclusion, pigs fed the diet containing DDGS had less digestibility of Lys, GE, ADF, NDF, and TDF than pigs fed the control diet. The digestibility of DM and GE was not influenced by collection period, but the concentration of VFA in cecal digesta and feces increased with the length of time pigs received the diets.


Activated platelet supernatant can augment the angiogenic potential of human peripheral blood stem cells mobilized from bone marrow by G-CSF.
Platelets not only play a role in hemostasis, but they also promote angiogenesis and tissue recovery by releasing various cytokines and making an angiogenic milieu. Here, we examined autologous 'activated platelet supernatant (APS)' as a priming agent for stem cells; thereby enhance their pro-angiogenic potential and efficacy of stem cell-based therapy for ischemic diseases. The mobilized peripheral blood stem cells ((mob)PBSCs) were isolated from healthy volunteers after subcutaneous injection of granulocyte-colony stimulating factor. APS was collected separately from the platelet rich plasma after activation by thrombin. (mob)PBSCs were primed for 6h before analysis. Compared to naive platelet supernatants, APS had a higher level of various cytokines, such as IL8, IL17, PDGF and VEGF. APS-priming for 6h induced (mob)PBSCs to express key angiogenic factors, surface markers (i.e. CD34, CD31, and CXCR4) and integrins (integrins α5, β1 and β2). Also (mob)PBSCs were polarized toward CD14(++)/CD16(+) pro-angiogenic monocytes. The priming effect was reproduced by an in vitro reconstruction of APS. Through this phenotype, APS-priming increased cell-cell adhesion and cell-extracellular matrix adhesion. The culture supernatant of APS-primed (mob)PBSCs contained high levels of IL8, IL10, IL17 and TNFα, and augmented proliferation and capillary network formation of human umbilical vein endothelial cells. In vivo transplantation of APS-primed (mob)PBSCs into athymic mice ischemic hindlimbs and Matrigel plugs elicited vessel differentiation and tissue repair. In safety analysis, platelet activity increased after mixing with (mob)PBSCs regardless of priming, which was normalized by aspirin treatment. Collectively, our data identify that APS-priming can enhance the angiogenic potential of (mob)PBSCs, which can be used as an adjunctive strategy to improve the efficacy of cell therapy for ischemic diseases.


MDMA-evoked changes in the binding of dopamine D(2) receptor ligands in striatum of rats with unilateral serotonin depletion.
We earlier reported an anomalous 50% decrease in [(11)C]N-methylspiperone ([(11)C]NMSP) binding to dopamine D(2)-like receptors in living pig striatum after challenge with 3,4-methylenedioxymethamphetamine (MDMA, "Ecstasy"), suggesting either (1) a species peculiarity in the vulnerability of butyrophenone binding to competition from dopamine or (2) a novel consequence of synergistic actions of serotonin and dopamine at dopamine receptors. To distinguish these possibilities, we used microPET to test the vulnerability of [(11)C]NMSP binding in striatum of rats with unilateral telencephalic serotonin lesions, later verified by [(125)I]RTI-55 autoradiography. Baseline [(11)C]NMSP microPET recordings were followed by either saline or MDMA-HCl (4 mg/kg) injections (i.v.), and a second [(11)C]NMSP recording, culminating with injection of [(3)H]raclopride for autoradiography ex vivo. Neither MDMA-challenge nor serotonin lesion had any detectable effect on [(11)C]NMSP binding. In contrast, MDMA challenge increased receptor occupancy by [(3)H]raclopride ex vivo (relative to the B(max) in vitro) from 8% to 12%, and doubled the free ligand concentration in cerebral cortex, apparently by blocking hepatic CYP2D6. Assuming a single binding-site model, the increased [(3)H]raclopride binding indicated doubling of the apparent equilibrium dissociation constant in vivo (K(app) (d)), revealing a 2-fold increase in competition from endogenous dopamine at [(3)H]raclopride binding sites. The results favor hypothesis (1) that the remarkable vulnerability of [(11)C]NMSP binding in pig striatum to MDMA challenge does not generalize to the rodent.


Microbial methane formation in deep aquifers of a coal-bearing sedimentary basin, Germany.
Coal-bearing sediments are major reservoirs of organic matter potentially available for methanogenic subsurface microbial communities. In this study the specific microbial community inside lignite-bearing sedimentary basin in Germany and its contribution to methanogenic hydrocarbon degradation processes was investigated. The stable isotope signature of methane measured in groundwater and coal-rich sediment samples indicated methanogenic activity. Analysis of 16S rRNA gene sequences showed the presence of methanogenic Archaea, predominantly belonging to the orders Methanosarcinales and Methanomicrobiales, capable of acetoclastic or hydrogenotrophic methanogenesis. Furthermore, we identified fermenting, sulfate-, nitrate-, and metal-reducing, or acetogenic Bacteria clustering within the phyla Proteobacteria, complemented by members of the classes Actinobacteria, and Clostridia. The indigenous microbial communities found in the groundwater as well as in the coal-rich sediments are able to degrade coal-derived organic components and to produce methane as the final product. Lignite-bearing sediments may be an important nutrient and energy source influencing larger compartments via groundwater transport.


Simultaneous enhancement of red upconversion luminescence and CT contrast of NaGdF4:Yb,Er nanoparticles via Lu3+ doping.
To date, lanthanide-doped upconversion nanoparticles (UCNPs) have been widely reported as a promising CT contrast agent because they have high atomic numbers and big X-ray attenuation coefficient values. However, it is still a challenge to fabricate a simple multimodal imaging probe with improved image quality for early cancer diagnosis in clinical medicine. Herein, ultra-small, uniform and monodisperse β-NaGdF4:Yb,Er,X% Lu (X = 0, 1, 2.5, 4, 6, 7.5) UCNPs were prepared through a solvothermal method with high-level modulation of both the phase and morphology. Meanwhile, a remarkably enhanced red upconversion luminescence (UCL) in the β-NaGdF4:Yb,Er,X% Lu NPs was successfully realized via Lu3+ doping. It is found that as the content of Lu3+ increases from 0 to 7.5 mol%, the UCL intensity of the red emission first increases and then decreases, with the optimum doping content of Lu3+ ions of 2.5 mol%. The red UCL enhancement is ascribed to the change of the Yb-Er interionic distance controlling the Yb-Er energy transfer rate and the distortion of the local environment of Er3+ ions influencing the 4f-4f transition rates of Er3+ ions, which has been further confirmed by the experimental check of the crystallographic phase and by photoluminescence spectroscopy employing Eu3+ as the structural probe, respectively. More importantly, after being modified with the HS-PEG2000-NH2 ligand, the NH2-PEGylated-NaGdF4:Yb,Er,X% Lu NPs exhibited low cytotoxicity, high biocompatibility, and remarkably enhanced contrast performance in in vitro UCL and in vivo CT imaging. On the basis of our findings, the as-obtained functionalized UCNPs could be considered as a promising versatile dual-mode imaging probe for bioimaging, tumor diagnosis, and cancer therapy.


Early mortality and AIDS progression despite high initial antiretroviral therapy adherence and virologic suppression in Botswana.
Adverse outcomes occurring early after antiretroviral therapy (ART) initiation are common in sub-Saharan Africa, despite reports of high levels of ART adherence in this setting. We sought to determine the relationship between very early ART adherence and early adverse outcomes in HIV-infected adults in Botswana. This prospective cohort study of 402 ART-naïve, HIV-infected adults initiating ART at a public HIV clinic in Gaborone, Botswana evaluated the relationship between suboptimal early ART adherence and HIV treatment outcomes in the initial months after ART initiation. Early adherence during the interval between initial ART dispensation and first ART refill was calculated using pill counts. In the primary analysis patients not returning to refill and those with adherence <0.95 were considered to have suboptimal early adherence. The primary outcome was death or loss to follow-up during the first 6 months of ART; a secondary composite outcome included the primary outcome plus incident opportunistic illness (OIs) and virologic failure. We also calculated the percent of early adverse outcomes theoretically attributable to suboptimal early adherence using the population attributable risk percent (PAR%). Suboptimal early adherence was independently associated with loss to follow-up and death (adjusted OR 2.3, 95% CI 1.1-4.8) and with the secondary composite outcome including incident OIs and virologic failure (adjusted OR 2.6, 95% CI 1.4-4.7). However, of those with early adverse outcomes, less than one-third had suboptimal adherence and approximately two-thirds achieved virologic suppression. The PAR% relating suboptimal early adherence and primary and secondary outcomes were 14.7% and 17.7%, respectively. Suboptimal early adherence was associated with poor outcomes, but most early adverse outcomes occurred in patients with optimal early adherence. Clinical care and research efforts should focus on understanding early adverse outcomes that occur despite optimal adherence.


Applying ontological realism to medically unexplained syndromes.
The past decade has witnessed an increased interest in what are called "medically unexplained syndromes" (MUS). We address the question of whether structuring the domain knowledge for MUS can be achieved by applying the principles of Ontological Realism in light of criticisms about their usefulness in areas where science has not yet led to insights univocally endorsed by the relevant communities. We analyzed whether the different perspectives held by MUS researchers can be represented without taking any particular stance and whether existing ontologies based on Ontological Realism can be further built upon. We did not find refutation of the applicability of the principles. We found the Ontology of General Medical Science and Information Artifact Ontology to provide useful frameworks for analyzing certain MUS controversies, although leaving other questions open.


The effects of patterned electrical stimulation combined with voluntary contraction on spinal reciprocal inhibition in healthy individuals.
The aim of this study was to examine the effects of voluntary contraction (VC) on the modulation of reciprocal inhibition induced by patterned electrical stimulation (PES) in healthy individuals. Twelve healthy volunteers participated in this study. PES was applied to the common peroneal nerve with a train of 10 pulses at 100 Hz every 2 s for 20 min. VC comprised repetitive ankle dorsiflexion at a frequency of 0.5 Hz for 20 min. All participants performed the following three tasks: (i) VC alone, (ii) PES alone, and (iii) PES combined with VC (PES+VC). Reciprocal inhibition was assessed using a soleus H-reflex conditioning-test paradigm at the time points of before, immediately after, 10 min after, 20 min after, and 30 min after the tasks. PES+VC increased the amount of reciprocal inhibition, with after-effects lasting up to 20 min. PES alone increased reciprocal inhibition and maintained the after-effects on reciprocal inhibition for 10 min, whereas VC alone increased only immediately after the task. VC could modulate the plastic changes in spinal reciprocal inhibition induced by PES in healthy individuals. PES combined with VC has a potential to modulate impaired reciprocal inhibition and it may facilitate functional recovery and improve locomotion after central nervous system lesions.


Generation of a Retinoblastoma (Rb)1-inducible dominant-negative (DN) mouse model.
Retinoblastoma 1 (Rb1) is an essential gene regulating cellular proliferation, differentiation, and homeostasis. To exert these functions, Rb1 is recruited and physically interacts with a growing variety of signaling pathways. While Rb1 does not appear to be ubiquitously expressed, its expression has been confirmed in a variety of hematopoietic and neuronal-derived cells, including the inner ear hair cells (HCs). Studies in transgenic mice demonstrate that complete germline or conditional Rb1 deletion leads to abnormal cell proliferation, followed by massive apoptosis; making it difficult to fully address Rb1's biochemical activities. To overcome these limitations, we developed a tetracycline-inducible TetO-CB-myc6-Rb1 (CBRb) mouse model to achieve transient and inducible dominant-negative (DN) inhibition of the endogenous RB1 protein. Our strategy involved fusing the Rb1 gene to the lysosomal protease pre-procathepsin B (CB), thus allowing for further routing of the DN-CBRb fusion protein and its interacting complexes for proteolytic degradation. Moreover, reversibility of the system is achieved upon suppression of doxycycline (Dox) administration. Preliminary characterization of DN-CBRb mice bred to a ubiquitous rtTA mouse line demonstrated a significant inhibition of the endogenous RB1 protein in the inner ear and in a number of other organs where RB1 is expressed. Examination of the postnatal (P) DN-CBRb mice inner ear at P10 and P28 showed the presence of supernumerary inner HCs (IHCs) in the lower turns of the cochleae, which corresponds to the described expression domain of the endogenous Rb1 gene. Selective and reversible suppression of gene expression is both an experimental tool for defining function and a potential means to medical therapy. Given the limitations associated with Rb1-null mice lethality, this model provides a valuable resource for understanding RB1 activity, relative contribution to HC regeneration and its potential therapeutic application.


Relating habitat and climatic niches in birds.
Predicting species' responses to the combined effects of habitat and climate changes has become a major challenge in ecology and conservation biology. However, the effects of climatic and habitat gradients on species distributions have generally been considered separately. Here, we explore the relationships between the habitat and thermal dimensions of the ecological niche in European common birds. Using data from the French Breeding Bird Survey, a large-scale bird monitoring program, we correlated the habitat and thermal positions and breadths of 74 bird species, controlling for life history traits and phylogeny. We found that cold climate species tend to have niche positions in closed habitats, as expected by the conjunction of the biogeographic history of birds' habitats, and their current continent-scale gradients. We also report a positive correlation between thermal and habitat niche breadths, a pattern consistent with macroecological predictions concerning the processes shaping species' distributions. Our results suggest that the relationships between the climatic and habitat components of the niche have to be taken into account to understand and predict changes in species' distributions.


Non-classical export of an adenovirus structural protein.
The icosahedral capsids of Adenoviruses (Ads) consist of the hexon and stabilizing proteins building the facettes, and of the vertex protein penton base (Pb) anchoring the protruding fibers. The fibers bind to the Coxsackie virus B Ad cell surface receptor (CAR) and Pb to integrins. Here we describe a novel property of the Ad2 Pb. Pb was found to leave the infected cell and, upon exit, it attached to the surrounding noninfected cells forming a radial gradient with highest Pb levels on cells adjacent to the infected cell. The producer cells remained intact until at least 30 h post infection. At this point, Pb was not recovered from the extracellular medium, suggesting that its cell-cell spread might not involve free Pb. When viral particles were released at late stages of infection, soluble Pb was found in the extracellular medium and it randomly bound to noninfected cells. Nonlytic export of Pb occurred upon transient transfection with plasmid DNA, but plasmid-encoded fiber was not exported, indicating that cell-cell spread of Pb is autonomous of infection. Pb export was not affected by Brefeldin A-induced disruption of the Golgi apparatus, suggesting that it occurred via a nonclassical mechanism. Interestingly, the coexpression of Pb and fiber leads to both Pb and fiber export, termed 'protein abduction'. We suggest that fiber abduction might support viral dissemination in infected tissues by interfering with tissue integrity.


Assessing the utility of COVID-19 case reports as a leading indicator for hospitalization forecasting in the United States.
Identifying data streams that can consistently improve the accuracy of epidemiological forecasting models is challenging. Using models designed to predict daily state-level hospital admissions due to COVID-19 in California and Massachusetts, we investigated whether incorporating COVID-19 case data systematically improved forecast accuracy. Additionally, we considered whether using case data aggregated by date of test or by date of report from a surveillance system made a difference to the forecast accuracy. Evaluating forecast accuracy in a test period, after first having selected the best-performing methods in a validation period, we found that overall the difference in accuracy between approaches was small, especially at forecast horizons of less than two weeks. However, forecasts from models using cases aggregated by test date showed lower accuracy at longer horizons and at key moments in the pandemic, such as the peak of the Omicron wave in January 2022. Overall, these results highlight the challenge of finding a modeling approach that can generate accurate forecasts of outbreak trends both during periods of relative stability and during periods that show rapid growth or decay of transmission rates. While COVID-19 case counts seem to be a natural choice to help predict COVID-19 hospitalizations, in practice any benefits we observed were small and inconsistent.


Implementation of health information technology in Veterans Health Administration to support transformational change: telehealth and personal health records.
The Institute of Medicine report, Crossing the Quality Chasm, called for significant improvements in 6 elements of healthcare performance: safety, effectiveness, patient centeredness, timeliness, efficiency, and equity. To meet the changing care needs of older veterans, many of whom are trying to manage the complexities of their chronic diseases in their own homes, the Veterans Health Administration (VHA) has promoted many of the Institute of Medicine elements by implementing health information technology (health IT), such as telehealth and a personal health record (PHR). To that end, approximately 5 years ago, VHA created the Office of Care Coordination and in particular a patient-centered Care Coordination/Home Telehealth (CCHT) program, which uses telehealth technologies (eg, messaging devices) to coordinate care directly from a patient's home to help self-manage their chronic diseases. VHA has also developed a PHR, My HealtheVet, which is a secure web-based portal that provides veterans the capability to access and manage health information. This article discusses the mechanisms by which these forms of health IT have been implemented to improve access to care and improve health. For telehealth, we present the outcomes from some of the published literature. For PHRs, we outline what is known to date and future research directions. The article also examines some structural, policy-related, and organizational barriers to health IT implementation and offers suggestions for future research.


Is PCR the Next Reference Standard for the Diagnosis of Schistosoma in Stool? A Comparison with Microscopy in Senegal and Kenya.
The current reference test for the detection of S. mansoni in endemic areas is stool microscopy based on one or more Kato-Katz stool smears. However, stool microscopy has several shortcomings that greatly affect the efficacy of current schistosomiasis control programs. A highly specific multiplex real-time polymerase chain reaction (PCR) targeting the Schistosoma internal transcriber-spacer-2 sequence (ITS2) was developed by our group a few years ago, but so far this PCR has been applied mostly on urine samples. Here, we performed more in-depth evaluation of the ITS2 PCR as an alternative method to standard microscopy for the detection and quantification of Schistosoma spp. in stool samples. Microscopy and PCR were performed in a Senegalese community (n = 197) in an area with high S. mansoni transmission and co-occurrence of S. haematobium, and in Kenyan schoolchildren (n = 760) from an area with comparatively low S. mansoni transmission. Despite the differences in Schistosoma endemicity the PCR performed very similarly in both areas; 13-15% more infections were detected by PCR when comparing to microscopy of a single stool sample. Even when 2-3 stool samples were used for microscopy, PCR on one stool sample detected more infections, especially in people with light-intensity infections and in children from low-risk schools. The low prevalence of soil-transmitted helminthiasis in both populations was confirmed by an additional multiplex PCR. The ITS2-based PCR was more sensitive than standard microscopy in detecting Schistosoma spp. This would be particularly useful for S. mansoni detection in low transmission areas, and post-control settings, and as such improve schistosomiasis control programs, epidemiological research, and quality control of microscopy. Moreover, it can be complemented with other (multiplex real-time) PCRs to detect a wider range of helminths and thus enhance effectiveness of current integrated control and elimination strategies for neglected tropical diseases.


Identification of Tyr residues that enhance folate substrate binding and constrain oscillation of the proton-coupled folate transporter (PCFT-SLC46A1).
The proton-coupled folate transporter (PCFT) mediates intestinal folate absorption and transport of folates across the choroid plexus. This study focuses on the role of Tyr residues in PCFT function. The substituted Cys-accessibility method identified four Tyr residues (Y291, Y362, Y315, and Y414) that are accessible to the extracellular compartment; three of these (Y291, Y362, and Y315) are located within or near the folate binding pocket. When the Tyr residues were replaced with Cys or Ala, these mutants showed similar (up to 6-fold) increases in influx Vmax and Kt/Ki for [(3)H]methotrexate and [(3)H]pemetrexed. When the Tyr residues were replaced with Phe, these changes were moderated or absent. When Y315A PCFT was used as representative of the mutants and [(3)H]pemetrexed as the transport substrate, this substitution did not increase the efflux rate constant. Furthermore, neither influx nor efflux mediated by Y315A PCFT was transstimulated by the presence of substrate in the opposite compartment; however, substantial bidirectional transstimulation of transport was mediated by wild-type PCFT. This resulted in a threefold greater efflux rate constant for cells that express wild-type PCFT than for cells that express Y315 PCFT under exchange conditions. These data suggest that these Tyr residues, possibly through their rigid side chains, secure the carrier in a high-affinity state for its folate substrates. However, this may be achieved at the expense of constraining the carrier's mobility, thereby decreasing the rate at which the protein oscillates between its conformational states. The Vmax generated by these Tyr mutants may be so rapid that further augmentation during transstimulation may not be possible.


Fast Triplet Formation via Singlet Exciton Fission in a Covalent Perylenediimide-β-apocarotene Dyad Aggregate.
A covalent dyad was synthesized in which perylene-3,4,:9:10-bis(dicarboximide) (PDI) is linked to β-apocarotene (Car) using a biphenyl spacer. The dyad is monomeric in toluene and forms a solution aggregate in methylcyclohexane (MCH). Using femtosecond transient absorption (fsTA) spectroscopy, the monomeric dyad and its aggregates were studied both in solution and in thin films. In toluene, photoexcitation at 530 nm preferentially excites PDI, and the dyad undergoes charge separation in τ = 1.7 ps and recombination in τ = 1.6 ns. In MCH and in thin solid films, 530 nm excitation of the PDI-Car aggregate also results in charge transfer that competes with energy transfer from (1)*PDI to Car and with an additional process, rapid Car triplet formation in <50 ps. Car triplet formation is only observed in the aggregated PDI-Car dyad and is attributed to singlet exciton fission (SF) within the aggregated PDI, followed by rapid triplet energy transfer from (3)*PDI to the carotenoid. SF from β-apocarotene aggregation is ruled out by direct excitation of Car films at 414 nm, where no triplet formation is observed. Time-resolved electron paramagnetic resonance measurements on aggregated PDI-Car show the formation of (3)*Car with a spin-polarization pattern that rules out radical-pair intersystem crossing as the mechanism of triplet formation as well.


Relationship of sense of coherence to stressful events, coping strategies, health status, and quality of life in women with breast cancer.
To test the hypothesis that Antonovsky's concept of sense of coherence (SOC) predicts stressful events, coping strategies, health status, and quality of life (QoL) in a cohort of postmenopausal women (n = 131) with newly diagnosed primary or recurrent breast cancer. Regression analyses of longitudinal data at baseline through 6 months following breast cancer diagnosis examined the relationships between SOC (13-item version), daily assessment of coping with stressful events, health status, and QoL (EORTC QLQ-30). The findings support Antonovsky's concept of SOC. Women with strong SOC reported fewer stressful events and more days without stressful events. They used more coping strategies and more frequently used distraction, situation redefinition, direct action, and relaxation, but seldom religion, to cope with stressful events, and reported better health status and QoL. Women with weak SOC experienced more distress and used fewer coping strategies, and they more frequently used coping strategies such as catharsis and seeking social and spiritual support, but seldom acceptance of the situation. They reported worse health status and QoL, regardless of disease stage or treatment. The relationships between SOC and health status and QoL were linear. Sense of coherence significantly predicts distress, number and type of coping strategies such as direct action and relaxation, health status, and QoL in women with breast cancer. Our data suggest that the SOC scale may be a useful screening tool to identify individuals particularly vulnerable to distress and unable to cope adequately. Assessing SOC strength may assist health care providers to provide individualized patient interventions.


Female harbor seal (Phoca vitulina) behavioral response to playbacks of underwater male acoustic advertisement displays.
During the breeding season, male harbor seals (Phoca vitulina) make underwater acoustic displays using vocalizations known as roars. These roars have been shown to function in territory establishment in some breeding areas and have been hypothesized to be important for female choice, but the function of these sounds remains unresolved. This study consisted of a series of playback experiments in which captive female harbor seals were exposed to recordings of male roars to determine if females respond to recordings of male vocalizations and whether or not they respond differently to roars from categories with different acoustic characteristics. The categories included roars with characteristics of dominant males (longest duration, lowest frequency), subordinate males (shortest duration, highest frequency), combinations of call parameters from dominant and subordinate males (long duration, high frequency and short duration, low frequency), and control playbacks of water noise and water noise with tonal signals in the same frequency range as male signals. Results indicate that overall females have a significantly higher level of response to playbacks that imitate male vocalizations when compared to control playbacks of water noise. Specifically, there was a higher level of response to playbacks representing dominant male vocalization when compared to the control playbacks. For most individuals, there was a greater response to playbacks representing dominant male vocalizations compared to playbacks representing subordinate male vocalizations; however, there was no statistical difference between those two playback types. Additionally, there was no difference between the playbacks of call parameter combinations and the controls. Investigating female preference for male harbor seal vocalizations is a critical step in understanding the harbor seal mating system and further studies expanding on this captive study will help shed light on this important issue.


Streamlined analysis schema for high-throughput identification of endogenous protein complexes.
Immunoprecipitation followed by mass spectrometry (IP/MS) has recently emerged as a preferred method in the analysis of protein complex components and cellular protein networks. Targeting endogenous protein complexes of higher eukaryotes, particularly in large-scale efforts, has been challenging due to cellular heterogeneity, high proteome complexity, and, compared to lower organisms, lack of efficient in-locus epitope-tagging techniques. It is further complicated by variability in nonspecific identifications and cross-reactivity of primary antibodies. Still, the study of endogenous human protein networks is highly desired despite its challenges. Here we describe a streamlined IP/MS protocol for the purification and identification of extended endogenous protein complexes. We investigate the sources of nonspecific protein binding and develop semiquantitative specificity filters that are based on peptide spectral count measurements. We also outline logical constraints for the derivation of accurate complex composition from IP/MS data and demonstrate the effectiveness of this approach by presenting our analyses of different transcriptional coregulator complexes. We show consistent purification of novel components for the Integrator complex, analyze the composition of the Mediator complex solely from our data to demonstrate the wide usability of spectral counts, and deconvolute heterogeneous HDAC1/2 networks into core complex modules and several novel subcomplex interactions.


Apalutamide for the Treatment of Nonmetastatic Castration-Resistant Prostate Cancer.
Prostate cancer is the fourth leading cause of cancer in the United States. Treatment of this oncologic disease involves a variety of different modalities including surgery, radiation, and systemic therapy. Systemic therapy is used for locally advanced and metastatic disease, and primarily involves hormonal blockade as a mechanism of disease control. Apalutamide is a nonsteroidal androgen receptor inhibitor that binds directly to the androgen receptor ligand binding-domain to prevent androgen receptor translocation. This agent is used in combination with gonadotropin-releasing hormone antagonists to shut down the production of testosterone through the reproductive system. It is the first drug to receive U.S. Food & Drug Administration approval for the treatment of nonmetastatic, castration-resistant prostate cancer. This article reviews the pharmacology of apalutamide along with its current place in therapy and management of associated adverse events.


Low-dose glucocorticoids suppresses ovarian tumor growth and metastasis in an immunocompetent syngeneic mouse model.
Ovarian cancer has the highest mortality rate among gynecologic malignancies. Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently with a poor prognosis. We previously reported a novel role of glucocorticoids (GCs) in metastatic ovarian cancer by upregulating microRNA-708. In this study, we used an immunocompetent syngeneic mouse model and further evaluated the effect and optimal dosages of GCs in treating metastatic ovarian cancer. The treatment of C57BL/6-derived ovarian cancer ID-8 cells with a synthetic GC, dexamethasone (DEX), induced the expression of microRNA-708, leading to decreased cell migration and invasion through targeting Rap1B. Administration of DEX at a low dose, as low as 5 μg/kg body weight, inhibited the primary tumor size and abdominal metastasis in mice bearing ID-8 cell-derived ovarian tumors. In the treated primary tumors, microRNA-708 was upregulated, whereas some proinflammatory cytokines, namely interleukin (IL)-1β and IL-18, were downregulated. The number of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment were reduced. Overall, our study shows that low-dose GCs can suppress ovarian cancer progression and metastasis likely through not only the upregulation of the metastasis suppressor microRNA-708, but also the modulation of TAMs and MDSCs in the tumor microenvironment.


NF-κB Enhances Androgen Receptor Expression through 5'-UTR Binding in Gingival Cells.
Dihydropyridine-induced gingival overgrowth (DIGO) is a side effect observed in patients treated for hypertension. The disease is aggravated by inflammation. Nifedipine (Nif), a dihydropyridine, causes gingival overgrowth by increasing the expression of the androgen receptor (AR). Furthermore, the proinflammatory cytokine interleukin 1β (IL-1β) induces collagen α1(I) expression through the AR in DIGO fibroblasts. These observations prompted us to investigate whether and how nuclear factor kappa B (NF-κB) affects AR expression in DIGO. Therefore, gingival fibroblasts obtained from the tissues of patients with DIGO and healthy subjects were stimulated with IL-1β, Nif, or both. mRNA and protein expression was detected with real-time polymerase chain reaction and Western blotting. High correlation coefficients were observed for the mRNA expression of the AR, connective tissue growth factor, and collagen α1(I) induced by both drugs. Western blot analysis showed that IL-1β and Nif increased and activated NF-κB more in DIGO cells than in healthy cells. An electrophoretic mobility shift assay demonstrated that the promoter and 5'-untranslated regions (5'-UTRs) of the AR gene contains 3 binding sites for the NF-κB p65 subunit. A chromatin immunoprecipitation assay revealed that the NF-κB p65 subunit was associated with AR 5'-UTRs in gingival fibroblasts. A site-directed mutagenesis study indicated that a mutation of NF-κB binding sites reduced Nif- and IL-1β-induced AR promoter activities. Collectively, these data indicate that NF-κB is an essential transcriptional regulator of AR gene expression and thus plays a crucial role in collagen overproduction in DIGO fibroblasts.


Causal mediation analysis in the context of clinical research.
Clinical researches usually collected numerous intermediate variables besides treatment and outcome. These variables are often incorrectly treated as confounding factors and are thus controlled using a variety of multivariable regression models depending on the types of outcome variable. However, these methods fail to disentangle underlying mediating processes. Causal mediation analysis (CMA) is a method to dissect total effect of a treatment into direct and indirect effect. The indirect effect is transmitted via mediator to the outcome. The mediation package is designed to perform CMA under the assumption of sequential ignorability. It reports average causal mediation effect (ACME), average direct effect (ADE) and total effect. Also, the package provides visualization tool for these estimated effects. Sensitivity analysis is designed to examine whether the results are robust to the violation of the sequential ignorability assumption since the assumption has been criticized to be too strong to be satisfied in research practice.


Dispersity effects in polymer self-assemblies: a matter of hierarchical control.
Advanced applications of polymeric self-assembled structures require a stringent degree of control over such aspects as functionality location, morphology and size of the resulting assemblies. A loss of control in the polymeric building blocks of these assemblies can have drastic effects upon the final morphology or function of these structures. Gaining precise control over various aspects of the polymers, such as chain lengths and architecture, blocking efficiency and compositional distribution is a challenge and, hence, measuring the intrinsic mass and size dispersity within these areas is an important aspect of such control. It is of great importance that a good handle on how to improve control and accurately measure it is achieved. Additionally dispersity of the final structure can also play a large part in the suitability for a desired application. In this Tutorial Review, we aim to highlight the different aspects of dispersity that are often overlooked and the effect that a lack of control can have on both the polymer and the final assembled structure.


Formation of cholesterol oxides in irradiated raw and cooked chicken meat during storage.
The objective of this study was to determine the effect of electron-beam irradiation on the oxidation of cholesterol in raw and cooked chicken meats with different packaging and storage times. Patties were prepared with skinless chicken breasts and legs. Half of the patties were used for raw meat study and the other half for cooked meat work. For cooked samples, patties were cooked in an electric oven to an internal temperature of 70 C. Raw and cooked meat patties were either aerobically or vacuum-packaged before irradiation. Irradiated patties were stored at 4 C up to 2 wk, and the amounts of cholesterol oxides in the patties were analyzed at 0, 7, and 14 d of storage. In raw chicken meat with vacuum packaging, 7beta-hydroxycholesterol and beta-epoxide were the only two cholesterol oxides present in significant amounts. In raw chicken meat with aerobic packaging, 7alpha-hydroxycholesterol and 7-keiocholesterol, which were not detected in vacuum-packaged raw chicken meat, were found. 7beta-Hydroxycholesterol in raw chicken meat was increased by irradiation and storage time, regardless of packaging. The kinds of cholesterol oxides found in cooked meat were basically the same as those found in raw chicken, but the levels in cooked meats at all storage time were higher than those of the raw meats. With vacuum packaging, irradiation had no consistent effect on the amount of beta-epoxide, 7alpha-hydroxycholesterol, or 7-ketocholesterol, but storage significantly influenced the amount of 7-ketocholesterol, 7beta-hydroxycholesterol, and total cholesterol oxides in cooked chicken meat. With aerobic packaging, irradiation significantly increased the formation of 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7-ketocholesterol in cooked meat stored for 0 and 7 d. After 14 d of storage, however, irradiation had minor effects on the formation of cholesterol oxides in aerobically packaged cooked chicken.


Deficiency of the Circadian Clock Gene Bmal1 Reduces Microglial Immunometabolism.
Microglia are brain immune cells responsible for immune surveillance. Microglial activation is, however, closely associated with neuroinflammation, neurodegeneration, and obesity. Therefore, it is critical that microglial immune response appropriately adapts to different stressors. The circadian clock controls the cellular process that involves the regulation of inflammation and energy hemostasis. Here, we observed a significant circadian variation in the expression of markers related to inflammation, nutrient utilization, and antioxidation in microglial cells isolated from mice. Furthermore, we found that the core clock gene-Brain and Muscle Arnt-like 1 (Bmal1) plays a role in regulating microglial immune function in mice and microglial BV-2 cells by using quantitative RT-PCR. Bmal1 deficiency decreased gene expression of pro-inflammatory cytokines, increased gene expression of antioxidative and anti-inflammatory factors in microglia. These changes were also observed in Bmal1 knock-down microglial BV-2 cells under lipopolysaccharide (LPS) and palmitic acid stimulations. Moreover, Bmal1 deficiency affected the expression of metabolic associated genes and metabolic processes, and increased phagocytic capacity in microglia. These findings suggest that Bmal1 is a key regulator in microglial immune response and cellular metabolism.


Argon mini-arc meets its match: use of a laser-driven plasma source in ultraviolet-detector calibrations.
The National Institute of Standards and Technology operates two spectral comparator facilities, both of which are used to provide detector calibrations from the ultraviolet to the near-infrared spectral range. One, the Ultraviolet Spectral Comparator Facility (UV SCF), has been in operation for more than two decades, providing one of the core calibration services. Recently, the illumination source used in the UV SCF has been changed from an argon mini-arc source to a laser-driven plasma light source. This new source has higher brightness, a smaller source size, better temporal stability, and much better conversion efficiency than the previous source. The improvements in the capabilities are summarized.


Effects of extended voluntary waiting period from calving until first insemination on body condition, milk yield, and lactation persistency.
A 1-yr calving interval (CInt) is usually associated with maximized milk output, due to the calving-related peak in milk yield. Extending CInt could benefit cow health and production efficiency due to fewer transition periods per unit of time. Extending CInt can affect lactation performance by fewer days dry per year, delayed pregnancy effect on milk yield, and greater milk solid yield in late lactation. This study first investigated the effects of 3 different voluntary waiting periods (VWP) from calving until first insemination on body weight, body condition, milk yield, and lactation persistency. Second, individual cow characteristics in early lactation were identified that contributed to milk yield and persistency of cows with different VWP. Holstein-Friesian dairy cows (n = 154) within 1 herd were blocked for parity, calving season, and expected milk yield. Cows were randomly assigned within the blocks to 1 of 3 VWP (50, 125, or 200 d: VWP50, VWP125, or VWP200, respectively) and monitored through 1 complete lactation and the first 6 wk of the subsequent lactation, or until culling. Minimum and mean CInt (384 vs. 452 vs. 501 d for VWP50 vs. VWP125 vs. VWP200) increased with increasing VWP, but maximum CInt was equal for the 3 VWP. Fat- and protein-corrected milk yield (FPCM) was analyzed weekly. Milk yield and FPCM were also expressed per day of CInt, to compare yields of cows with different VWP. Persistency was determined between d 100 and d 200 of the lactation, as well as between d 100 and dry-off. Values are presented as least squares means ± standard error of the mean. During the first 44 wk of lactation, VWP did not affect FPCM yield in both primiparous and multiparous cows. The VWP did not affect milk yield per day of CInt. The VWP did not affect FPCM yield per day of calving interval for primiparous cows. Multiparous cows in VWP125 had FPCM yield per day of CInt similar to that of VWP50. Multiparous cows in VWP200 had lower FPCM yield per day of CInt compared with VWP50 (27.2 vs. 30.4 kg/d). During the last 6 wk before dry-off, cows in VWP125 had lower yield compared with cows in VWP50, which could benefit their udder health in the dry period and after calving. Persistency was better for cows in VWP200 compared with cows in VWP50 (-0.05 vs. -0.07 kg/d). Body weight was not different among VWP groups. Multiparous cows in VWP200 had a higher body condition score in the last 3 mo before dry-off and the first 6 wk of the next lactation, compared with multiparous cows in VWP125 and VWP50. The VWP could be extended from 50 d to 125 d without an effect on daily yield per day of calving interval. Extending VWP until 200 d for primiparous cows did not affect their daily milk yield, but multiparous cows with a 200-d VWP had a reduced milk yield per day of calving interval and an increased body condition in late lactation and the subsequent lactation, compared with multiparous cows with a 50-d VWP.


Ectoplasmic specialization, a testis-specific cell-cell actin-based adherens junction type: is this a potential target for male contraceptive development?
The seminiferous tubule of the mammalian testis is largely composed of Sertoli and germ cells, which coordinate with Leydig cells in the interstitium and perform two major physiological functions, namely spermatogenesis and steroidogenesis respectively. Each tubule is morphologically divided into (i) the seminiferous epithelium composing Sertoli and germ cells, and (ii) the basement membrane (a modified form of extracellular matrix); underneath this lies the collagen fibril network, the myoid cell layer, and the lymphatic vessel, which collectively constitute the tunica propia. In the seminiferous epithelium, of rodent testes each type A1 spermatogonium (diploid, 2n) differentiates into 256 elongated spermatids (haploid, 1n) during spermatogenesis. Additionally, developing germ cells must migrate progressively from the basal to the luminal edge of the adluminal compartment so that fully developed spermatids can be released into the lumen at spermiation. Without this timely event of cell movement, spermatogenesis cannot reach completion and infertility will result. Yet developing round elongating/elongated spermatids must remain attached to the epithelium via a specialized Sertoli-germ cell actin-based adherens junction (AJ) type known as ectoplasmic specialization (ES), which is crucial not only for cell attachment but also for spermatid movement and orientation in the epithelium. However, the biochemical composition and molecular architecture of the protein complexes that constitute the ES have only recently been studied. Furthermore, the signalling pathways that regulate ES dynamics are virtually unknown. This review highlights recent advances in these two areas of research. It is expected that, if adequately expanded, these studies should yield new insights into the development of novel contraceptives targeted to perturb ES function in the testis. The potential to specifically target the ES may also mean that contraceptive action could be achieved without perturbing the hypothalamic-pituitary-testicular axis.


Differential cellular responses in healthy mice and in mice with established airway inflammation when exposed to hematite nanoparticles.
The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.


Pornography actresses: an assessment of the damaged goods hypothesis.
The damaged goods hypothesis posits that female performers in the adult entertainment industry have higher rates of childhood sexual abuse (CSA), psychological problems, and drug use compared to the typical woman. The present study compared the self-reports of 177 porn actresses to a sample of women matched on age, ethnicity, and marital status. Comparisons were conducted on sexual behaviors and attitudes, self-esteem, quality of life, and drug use. Porn actresses were more likely to identify as bisexual, first had sex at an earlier age, had more sexual partners, were more concerned about contracting a sexually transmitted disease (STD), and enjoyed sex more than the matched sample, although there were no differences in incidence of CSA. In terms of psychological characteristics, porn actresses had higher levels of self-esteem, positive feelings, social support, sexual satisfaction, and spirituality compared to the matched group. Last, female performers were more likely to have ever used 10 different types of drugs compared to the comparison group. A discriminant function analysis was able to correctly classify 83% of the participants concerning whether they were a porn actress or member of the matched sample. These findings did not provide support for the damaged goods hypothesis.