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As the US transitions to a majority–minority population, the underrepresentation in the science, technology, engineering, and mathematics (STEM) workforce must be resolved to ensure that our nation maintains its competitiveness and global economic advantage. The persistent problem of retaining underrepresented minority (URM) students in STEM continues to be a national priority after several decades of attention. The role of historically black colleges and universities (HBCUs) in addressing this challenge cannot be overstated, given their history in producing African American STEM graduates. As the largest HBCU in the country, North Carolina A&T State University (NC A&T) serves a combined undergraduate and graduate population of 11,877 students, 78% of which self-identify as African American. To overcome the multiple challenges that impede retention and persistence to degree completion in biology, the Department of Biology at NC A&T has adopted a major cultural shift in its advising strategy. The new approach encompasses a Life Mapping and Advising Model that builds faculty–student relationships and engages both parties effectively in the process. The model includes six important pillars to drive student success: (1) dedicated advising space, the Life Mapping and Advising Center (LMAC), (2) effective advisors, (3) integrated peer mentor and peer tutoring programs, (4) an intrusive advising strategy, (5) integration with first-year student success courses, and (6) life coaching. Although the program is in its infancy, based on the first-year assessment data, we have observed many promising trends that, together, point toward successful retention and persistence of our students in the major.

Many members of the G protein-coupled receptor family, including examples with clear therapeutic potential, remain poorly characterised. This often reflects limited availability of suitable tool ligands with which to interrogate receptor function. In the case of GPR84, currently a target for the treatment of idiopathic pulmonary fibrosis, recent times have seen the description of novel orthosteric and allosteric agonists. Using 2-(hexylthiol)pyrimidine-4,6 diol (2-HTP) and di(5,7-difluoro-1H-indole-3-yl)methane (PSB-16671) as exemplars of each class, in cell lines transfected to express either human or mouse GPR84, both ligands acted as effective on-target activators and with high co-operativity in their interactions. This was also the case in lipopolysaccharide-activated model human and mouse immune cell lines. However in mouse bone-marrow-derived neutrophils, where expression of GPR84 is particularly high, the capacity of PSB-16671 but not of 2-HTP to promote G protein activation was predominantly off-target because it was not blocked by an antagonist of GPR84 and was preserved in neutrophils isolated from GPR84 deficient mice. These results illustrate the challenges of attempting to study and define functions of poorly characterised receptors using ligands that have been developed via medicinal chemistry programmes, but where assessed activity has been limited largely to the initially identified target.

African Americans are disproportionately burdened by diabetic kidney disease (DKD). However, little is known about the cellular and molecular mechanisms underlying the onset and progression of DKD in this population. The goal of the current study was to determine the association between specific inflammation markers and kidney injury in diabetic African American men. To this end, we recruited diabetic patients either with (n=20) or without (n=87) diagnosed kidney disease along with age-matched nondiabetic controls (n=81). Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filtration rates (eGFR) were used for biochemical assessment of kidney function. We then measured plasma and urinary levels of seven inflammatory markers, including adiponectin, C-reactive protein (CRP), tumor necrosis factor-α(TNF-α), TNF receptor 1 (TNFR1), TNF receptor 2 (TNFR2), interleukin-6 (IL-6), and intercellular cell adhesion molecule-1 (ICAM-1). Plasma levels of TNF-α, TNFR1, and TNFR2 were significantly higher in diabetics with macroalbuminuria compared to nondiabetic controls and diabetics with normoalbuminuria or microalbuminuria. Likewise, urinary levels of ICAM-1 were higher in diabetics with macroalbuminuria compared to the other groups. Indeed, urinary ICAM-1, plasma TNF-α, and adiponectin had moderate positive correlations with UACR while plasma TNFR1 and TNFR2 levels were strongly correlated with kidney injury, indicated by multiple biomarkers of kidney injury. In contrast, though plasma CRP was elevated in diabetic subjects relative to nondiabetic controls, its levels did not correlate with kidney injury. Together, these data suggest that inflammation, particularly that mediated by the TNF-α/NF-κB signaling axis, may play a role in the pathogenesis of DKD in African American men.

Live bird markets (LBMs) are major targets for avian influenza virus (AIV) surveillance programmes. While sampling the LBM environment has become a widely used alternative to the labour-intensive sampling of live poultry, the design of surveillance programmes and the interpretation of their results are compromised by the lack of knowledge about the effectiveness of these sampling strategies. We used latent class models and a unique empirical dataset collated in Vietnamese LBMs to estimate the sensitivity and specificity of five different sample types for detecting AIVs subtypes H5N1 and H5N6: oropharyngeal duck samples, solid and liquid wastes, poultry drinking water and faeces. Results suggest that the sensitivity of environmental samples for detecting H5N1 viruses is equivalent to that of oropharyngeal duck samples; however, taking oropharyngeal duck samples was estimated to be more effective in detecting H5N6 viruses than taking any of the four environmental samples. This study also stressed that the specificity of the current surveillance strategy in LBMs was not optimal leading to some false positive LBMs. Using simulations, we identified 42 sampling strategies more parsimonious than the current strategy and expected to be highly sensitive for both viruses at the LBM level. All of these strategies involved the collection of both environmental and oropharyngeal duck samples.

Levodopa-induced dyskinesias (LID) are a prevalent side effect of chronic treatment with levodopa (L-DOPA) for the motor symptoms of Parkinson’s disease (PD). It has long been hypothesized that serotonergic neurons of the dorsal raphe nucleus (DRN) are capable of L-DOPA uptake and dysregulated release of dopamine (DA), and that this “false neurotransmission” phenomenon is a main contributor to LID development. Indeed, many preclinical studies have demonstrated LID management with serotonin receptor agonist treatment, but unfortunately, promising preclinical data has not been translated in large-scale clinical trials. Importantly, while there is an abundance of convincing clinical and preclinical evidence supporting a role of maladaptive serotonergic neurotransmission in LID expression, there is no direct evidence that dysregulated DA release from serotonergic neurons impacts LID formation. In this study, we ectopically expressed the DA autoreceptor D2Rs (or GFP) in the DRN of 6-hydroxydopamine (6-OHDA) lesioned rats. No negative impact on the therapeutic efficacy of L-DOPA was seen with rAAV-D2Rs therapy. However, D2Rs treated animals, when subjected to a LID-inducing dose regimen of L-DOPA, remained completely resistant to LID, even at high doses. Moreover, the same subjects remained resistant to LID formation when treated with direct DA receptor agonists, suggesting D2Rs activity in the DRN blocked dyskinesogenic L-DOPA priming of striatal neurons. In vivo microdialysis confirmed that DA efflux in the striatum was reduced with rAAV-D2Rs treatment, providing explicit evidence that abnormal DA release from DRN neurons can affect LID. This is the first direct evidence of dopaminergic neurotransmission in DRN neurons and its modulation with rAAV-D2Rs gene therapy confirms the serotonin hypothesis in LID, demonstrating that regulation of serotonergic neurons achieved with a gene therapy approach offers a novel and potent antidyskinetic therapy. Electronic supplementary material The online version of this article (10.1186/s40478-018-0653-7) contains supplementary material, which is available to authorized users.

BACKGROUND. Pulmonary arterial hypertension (PAH) is a deadly disease of the small pulmonary vasculature with an increased prevalence of insulin resistance (IR). Insulin regulates both glucose and lipid homeostasis. We sought to quantify glucose- and lipid-related IR in human PAH, testing the hypothesis that lipoprotein indices are more sensitive indices of IR in PAH. METHODS. Oral glucose tolerance testing in PAH patients and triglyceride-matched (TG-matched) controls and proteomic, metabolomics, and lipoprotein analyses were performed in PAH and controls. Results were validated in an external cohort and in explanted human PAH lungs. RESULTS. PAH patients were similarly glucose intolerant or IR by glucose homeostasis metrics compared with control patients when matched for the metabolic syndrome. Using the insulin-sensitive lipoprotein index, TG/HDL ratio, PAH patients were more commonly IR than controls. Proteomic and metabolomic analysis demonstrated separation between PAH and controls, driven by differences in lipid species. We observed a significant increase in long-chain acylcarnitines, phosphatidylcholines, insulin metabolism–related proteins, and in oxidized LDL receptor 1 (OLR1) in PAH plasma in both a discovery and validation cohort. PAH patients had higher lipoprotein axis–related IR and lipoprotein-based inflammation scores compared with controls. PAH patient lung tissue showed enhanced OLR1 immunostaining within plexiform lesions and oxidized LDL accumulation within macrophages. CONCLUSIONS. IR in PAH is characterized by alterations in lipid and lipoprotein homeostasis axes, manifest by elevated TG/HDL ratio, and elevated circulating medium- and long-chain acylcarnitines and lipoproteins. Oxidized LDL and its receptor OLR1 may play a role in a proinflammatory phenotype in PAH. FUNDING. NIH {"type":"entrez-nucleotide","attrs":{"text":"DK096994","term_id":"187460004"}}DK096994, {"type":"entrez-nucleotide","attrs":{"text":"HL060906","term_id":"1051598402"}}HL060906, UL1 RR024975-01, UL1 TR000445-06, {"type":"entrez-nucleotide","attrs":{"text":"DK020593","term_id":"187398843"}}DK020593, P01 HL108800-01A1, and UL1 TR002243; American Heart Association 13FTF16070002.

The effect of methoxy and hydroxy substitutions in different positions of the phenoxy moiety of the N-((6,6-diphenyl-1,4-dioxan-2-yl)methyl)-2-phenoxyethan-1-amine scaffold on the affinity/activity for D(2)-like, 5-HT(1A) and α(1)-adrenoceptor subtypes was evaluated. Multitarget compounds with suitable combinations of dopaminergic and serotoninergic profiles were discovered. In particular, the 2-methoxy derivative 3 showed a multitarget combination of 5-HT(1A)/D(4) agonism and D(2)/D(3)/5-HT(2A) antagonism, which may be a favorable profile for the treatment of schizophrenia. Interestingly, the 3-hydroxy derivative 8 behaved as a partial agonist at D(2) and as a potent full agonist at D(3) and D(4) subtypes. In addition to its potent 5-HT(1A) receptor agonism, such a dopaminergic profile makes 8 a potential multitarget compound for the treatment of Parkinson’s disease (PD). Indeed, the activation of 5-HT(1A) receptors might be helpful in reducing dyskinetic side effects associated with dopaminergic stimulation.

Aim: Animal movement is an important determinant of individual survival, population dynamics and ecosystem structure and function. Nonetheless, it is still unclear how local movements are related to resource availability and the spatial arrangement of resources. Using resident bird species and migratory bird species outside the migratory period, we examined how the distribution of resources affects the movement patterns of both large terrestrial birds (e.g., raptors, bustards and hornbills) and waterbirds (e.g., cranes, storks, ducks, geese and flamingos). Location: Global. Time period: 2003–2015. Major taxa studied: Birds. Methods: We compiled GPS tracking data for 386 individuals across 36 bird species. We calculated the straight‐line distance between GPS locations of each individual at the 1‐hr and 10‐day time‐scales. For each individual and time‐scale, we calculated the median and 0.95 quantile of displacement. We used linear mixed‐effects models to examine the effect of the spatial arrangement of resources, measured as enhanced vegetation index homogeneity, on avian movements, while accounting for mean resource availability, body mass, diet, flight type, migratory status and taxonomy and spatial autocorrelation. Results: We found a significant effect of resource spatial arrangement at the 1‐hr and 10‐day time‐scales. On average, individual movements were seven times longer in environments with homogeneously distributed resources compared with areas of low resource homogeneity. Contrary to previous work, we found no significant effect of resource availability, diet, flight type, migratory status or body mass on the non‐migratory movements of birds. Main conclusions: We suggest that longer movements in homogeneous environments might reflect the need for different habitat types associated with foraging and reproduction. This highlights the importance of landscape complementarity, where habitat patches within a landscape include a range of different, yet complementary resources. As habitat homogenization increases, it might force birds to travel increasingly longer distances to meet their diverse needs. National Trust for Scotland; Penguin Foundation; The U.S. Department of Energy, Grant/Award Number: DE-EE0005362; Australian Research Council; NASA's Arctic Boreal Vulnerability Experiment (ABoVE), Grant/Award Number: NNX15AV92A; Netherlands Organization for Scientific Research, Grant/Award Number: VIDI 864.10.006; BCC; NSF Award, Grant/Award Number: ABI-1458748; U.K. Department for Energy and Climate Change; ‘Juan de la Cierva ‐ Incorporación’ postdoctoral grant; Irish Research Council, Grant/Award Number: GOIPD/2015/81 ; DECC; Goethe International Postdoctoral Programme, People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme FP7/2007‐2013/ under REA grant agreement no [291776]; German Aerospace Center Award, Grant/Award Number: 50JR1601; Scottish Natural Heritage; Solway Coast AONB Sustainable Development Fund; COWRIE Ltd.; Heritage Lottery Fund; Robert Bosch Stiftung; NSF Division of Biological Infrastructure Award, Grant/Award Number: 1564380; Spanish Ministry of Economy and Competitiveness, Grant/Award Number: IJCI-2014-19190; Energinet.dk; NASA Award, Grant/Award Number: NNX15AV92A; MAVA Foundation; Fundação para a Ciência e Tecnologia, Grant/Award Number: SFRH/BPD/118635/2016; National Key R&D Program of China, Grant/Award Number: 2016YFC0500406; Green Fund of the Greek Ministry of Environment

Prebiotics are nondigestible food ingredients that have beneficial effects on human health. Recently, these ingredients have garnered increasing attention, particularly for their role in feeding beneficial bacteria within the gastrointestinal tract. In addition, synbiotic (combination of pre- and probiotics) approaches have been studied as therapeutic strategies in several clinical conditions and have shown the potential to improve host health. This chapter provides an overview of how prebiotics and synbiotics can modulate the gut microbiota within the context of disease prevention and the promotion of good health. The chapter also highlights the concerns regarding potential stimulating effect of prebiotics on other harmful bacteria.

Background ONC201 is a small molecule antagonist of DRD2, a G protein-coupled receptor overexpressed in several malignancies, that has prolonged antitumor efficacy and immunomodulatory properties in preclinical models. The first-in-human trial of ONC201 previously established a recommended phase II dose (RP2D) of 625 mg once every three weeks. Here, we report the results of a phase I study that evaluated the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of weekly ONC201. Methods Patients ≥ 18 years old with an advanced solid tumor refractory to standard treatment were enrolled. Dose escalation proceeded with a 3 + 3 design from 375 mg to 625 mg of ONC201. One cycle, also the dose-limiting toxicity (DLT) window, was 21 days. The primary endpoint was to determine the RP2D of weekly ONC201, which was confirmed in an 11-patient dose expansion cohort. Results Twenty patients were enrolled: three at 375 mg and 17 at 625 mg of ONC201. The RP2D was defined as 625 mg with no DLT, treatment discontinuation, or dose modifications due to drug-related toxicity. PK profiles were consistent with every-three-week dosing and similar between the first and fourth dose. Serum prolactin and caspase-cleaved cytokeratin-18 induction were detected, along with intratumoral integrated stress response activation and infiltration of granzyme B+ Natural Killer cells. Induction of immune cytokines and effectors was higher in patients who received ONC201 once weekly versus once every three weeks. Stable disease of > 6 months was observed in several prostate and endometrial cancer patients. Conclusions Weekly, oral ONC201 is well-tolerated and results in enhanced immunostimulatory activity that warrants further investigation. Trial registration NCT02250781 (Oral ONC201 in Treating Patients With Advanced Solid Tumors), NCT02324621 (Continuation of Oral ONC201 in Treating Patients With Advanced Solid Tumors). Electronic supplementary material The online version of this article (10.1186/s40425-019-0599-8) contains supplementary material, which is available to authorized users.

The dopamine D(3) receptor (D(3)R) has emerged as a promising pharmacotherapeutic target for the treatment of several diseases including schizophrenia, Parkinson’s disease, and substance use disorders. However, studies investigating the D(3)R’s precise role in dopamine neurotransmission or how it may be exploited to modulate responses to drugs of abuse have produced contrasting results, in part because most D(3)R-targeted compounds often also interact with D(2) receptors (D(2)R). To resolve this issue, we set out to systematically characterize and compare the consequences of selective D(2)R or D(3)R antagonists on the behavioral-stimulant properties of cocaine in mice, and to identify putative neurobiological mechanisms underlying their behavior-modifying effects. Pretreatment with the selective D(2)R antagonist L-741,626 attenuated, while pretreatment with the selective D(3)R antagonist PG01037 enhanced, the locomotor-activating effects of both acute cocaine administration as well as sensitization following repeated cocaine dosing. While both antagonists potentiated cocaine-induced increases in presynaptic dopamine release, we report for the first time that D(3)R blockade uniquely facilitated dopamine-mediated excitation of D(1)-expressing medium spiny neurons in the nucleus accumbens. Collectively, our results demonstrate that selective D(3)R antagonism potentiates the behavioral-stimulant effects of cocaine in mice, an effect that is in direct opposition to that produced by selective D(2)R antagonism or nonselective D(2)-like receptor antagonists, and is likely mediated by facilitating D(1)-mediated excitation in the nucleus accumbens. These findings provide novel insights into the neuropharmacological actions of D(3)R antagonists on mesolimbic dopamine neurotransmission and their potential utility as pharmacotherapeutics.

Despite their classification as low pathogenicity avian influenza viruses (LPAIV), A/H9N2 viruses cause significant losses in poultry in many countries throughout Asia, the Middle East and North Africa. To date, poultry surveillance in Vietnam has focused on detection of influenza H5 viruses, and there is limited understanding of influenza H9 epidemiology and transmission dynamics. We determined prevalence and diversity of influenza A viruses in chickens from live bird markets (LBM) of 7 northern Vietnamese provinces, using pooled oropharyngeal swabs collected from October to December 2014. Screening by real time RT-PCR revealed 1207/4900 (24.6%) of pooled swabs to be influenza A virus positive; overall prevalence estimates after accounting for pooling (5 swabs/pools) were 5.8% (CI 5.4–6.0). Subtyping was performed on 468 pooled swabs with M gene Ct, Highlights • We report detection of highly pathogenic avian influenza (HPAI) from healthy chickens in Live Bird Markets of Vietnam. Because all breeds of domestic chickens are extremely susceptible to HPAI, we speculate that HPAI detections from market chickens may reflect infections that occur after arrival in the market. Alternatively, shedding of HPAI from healthy birds may reflect vaccine-induced protective immunity that mitigates disease but does not block viral infection. • As many as 49% of all pooled surveillance swabs were positive for influenza A virus, corresponding to an overall Influenza A prevalence of 5.45% (95% Confidence Interval 5.4-6.0%). • Low pathogenicity avian influenza (LPAI) H9N2 accounted for the vast majority of all influenza A detections in market chickens sampled from 9 northern provinces. • To date there is no evidence to suggest an interaction effect between circulation of H5 and H9 viruses; however sampling strategies that involve pooling of surveillance swabs from multiple birds greatly complicates the assessment of co-infection rates or evaluation of epidemiological associations.

Although commonly encountered, patients with combined postcapillary and precapillary pulmonary hypertension (Cpc-PH) have poorly understood pulmonary vascular properties. The product of pulmonary vascular resistance and compliance, resistance-compliance (RC) time, is a measure of pulmonary vascular physiology. While RC time is lower in postcapillary PH than in precapillary PH, the RC time in Cpc-PH and the effect of pulmonary wedge pressure (PWP) on RC time are unknown. We tested the hypothesis that Cpc-PH has an RC time that resembles that in pulmonary arterial hypertension (PAH) more than that in isolated postcapillary PH (Ipc-PH). We analyzed the hemodynamics of 282 consecutive patients with PH referred for right heart catheterization (RHC) with a fluid challenge from 2004 to 2013 (cohort A) and 4,382 patients who underwent RHC between 1998 and 2014 for validation (cohort B). Baseline RC time in Cpc-PH was higher than that in Ipc-PH and lower than that in PAH in both cohorts (P < 0.001). In cohort A, RC time decreased after fluid challenge in patients with Ipc-PH but not in those with PAH or Cpc-PH (P < 0.001). In cohort B, the inverse relationship of pulmonary vascular compliance and resistance, as well as that of RC time and PWP, in Cpc-PH was similar to that in PAH and distinct from that in Ipc-PH. Our findings demonstrate that patients with Cpc-PH have pulmonary vascular physiology that resembles that of patients with PAH more than that of Ipc-PH patients. Further study is warranted to identify determinants of vascular remodeling and assess therapeutic response in this subset of PH.

Agro-ecological conditions associated with the spread and persistence of highly pathogenic avian influenza (HPAI) are not well understood, but the trade of live poultry is suspected to be a major pathway. Although market chains of live bird trade have been studied through indirect means including interviews and questionnaires, direct methods have not been used to identify movements of individual poultry. To bridge the knowledge gap on quantitative movement and transportation of poultry, we introduced a novel approach for applying telemetry to document domestic duck movements from source farms at Poyang Lake, China. We deployed recently developed transmitters that record Global Positioning System (GPS) locations and send them through the Groupe Special Mobile (GSM) cellular telephone system. For the first time, we were able to track individually marked ducks from 3 to 396 km from their origin to other farms, distribution facilities, or live bird markets. Our proof of concept test showed that the use of GPS-GSM transmitters may provide direct, quantitative information to document the movement of poultry and reveal their market chains. Our findings provide an initial indication of the complexity of source-market network connectivity and highlight the great potential for future telemetry studies in poultry network analyses. published

Although the economic benefits of biomass heating in rural regions have been widely asserted, few studies have conducted a thorough economic impact analysis within the United States. This study proposes biomass district heating (BDH) as a means to stimulate the rural economy of the Tug Hill region of New York State by establishing a local industry and providing lower cost heat compared to the local alternative, #2 fuel oil, and examines the associated economic impacts. Since there are no BDH networks endogenous to the region, an expenditure pattern approach to input–output analysis is employed. The $11.4 million spent annually over the 20 year project payment period on the construction, biomass procurement, and production of heat with BDH would generate $18.7 million in local economic activity and create 143 jobs throughout the three county model region; a significant impact if concentrated around the rural study villages. These impacts are comparable, but less than, those modeled by other studies in countries with more established BDH networks. However, the precision of the impacts generated by the model are tempered by the significant discrepancy between the study region and the three county model region which included several larger urban areas. Ultimately, the limitations associated with the model scale and the absence of established expenditure patterns inhibit major conclusions in regards to the discreet impacts of BDH to the study villages, although a significant portion of the annual impacts estimated can be expected to occur in the villages given the location of the BDH networks.

Proton magnetic resonance (MR) imaging at 300 MHz was used to characterise the dewatering of Pinus radiata sapwood. The sapwood was immersed in CO 2 that was cycled at temperatures greater than 31 °C between gas (0.1–6 MPa) and supercritical fluid (15–20 MPa) phase. A combination of FLASH and RARE pulse sequences were used to highlight differences in T 2 *( H ) and T 2 ( H ) relaxation. It was observed that CO 2 entered into the green sapwood via air or water vapour-filled cells in the latewood and then diffused into earlywood cells adjacent to the pith side of the latewood bands. The dissolved CO 2 reduced the surface tension of water which facilitated the expulsion of sap. As the pressure was released, and CO 2 bubbles formed and expanded, the sap flowed tangentially towards the surfaces. This accounted, in part, for the observed independence of sample size on the supercritical CO 2 dewatering process.

Previously, management of hypertension has concentrated on lowering elevated blood pressure. However, the target has shifted to reducing absolute cardiovascular (CV) risk. It is estimated that two in three Australian adults have three or more CV risk factors at the same time. Moderate reductions in several risk factors can, therefore, be more effective than major reductions in one. When managing hypertension, therapy should be focused on medications with the strongest evidence for CV event reduction, substituting alternatives only when a primary choice is not appropriate. Hypertension management guidelines categorise angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) interchangeably as first-line treatments in uncomplicated hypertension. These medications have different mechanisms of action and quite different evidence bases. They are not interchangeable and their prescription should be based on clinical evidence. Despite this, currently ARB prescriptions are increasing at a higher rate than those for ACEI and other antihypertensive classes. Evidence that ACEI therapy prevents CV events and death, in patients with coronary artery disease or multiple CV risk factors, emerged from the European trial on reduction of cardiac events with perindopril in stable coronary artery disease (EUROPA) and Heart Outcomes Prevention Evaluation (HOPE) trials respectively. The consistent benefit has been demonstrated in meta-analyses. The clinical trial data for ARB are less consistent, particularly regarding CV outcomes and mortality benefit. The evidence supports the use of ACEI (Class 1a) compared with ARB despite current prescribing trends.

Protein hydroxylation is an emerging posttranslational modification involved in both normal cellular processes and a growing number of pathological states, including several cancers. Protein hydroxylation is mediated by members of the hydroxylase family of enzymes, which catalyze the conversion of an alkyne group at select lysine or proline residues on their target substrates to a hydroxyl. Traditionally, hydroxylation has been identified using expensive and time-consuming experimental methods, such as tandem mass spectrometry. Therefore, to facilitate identification of putative hydroxylation sites and to complement existing experimental approaches, computational methods designed to predict the hydroxylation sites in protein sequences have recently been developed. Building on these efforts, we have developed a new method, termed RF-Hydroxysite, that uses random forest to identify putative hydroxylysine and hydroxyproline residues in proteins using only the primary amino acid sequence as input. RF-Hydroxysite integrates features previously shown to contribute to hydroxylation site prediction with several new features that we found to augment the performance remarkably. These include features that capture physicochemical, structural, sequence-order and evolutionary information from the protein sequences. The features used in the final model were selected based on their contribution to the prediction. Physicochemical information was found to contribute the most to the model. The present study also sheds light on the contribution of evolutionary, sequence order, and protein disordered region information to hydroxylation site prediction. The web server for RF-Hydroxysite is available online at http://bcb.ncat.edu/RF_hydroxy/.

As of September 2013, federal and state governments had nearly 500 policies to support production of electricity and heat from forest biomass. This research used a four-tier classification structure to categorize policy instruments used in these policies based on: approach (incentive, regulation, information), type (e.g. tax incentive), subcategory (e.g. tax exemption), and specification (e.g. sales tax exemption). More (113) of these policies were enacted in 2007 and 2008, more than in any other two-year period, and there was a significant increase in the number of forest bioenergy (46) and biomass specific (36) policies by 2013. Cluster analysis provided evidence that neighboring states adopted similar numbers and types of policies. Oregon (in cluster by itself) had the highest number of tax incentives and biomass-specific policies, while most Southern, Southeast, Southern Appalachia and Midwestern states (the most dissimilar cluster to Oregon) had a limited number of policies. Most states in remaining clusters offered a mix of integrated policies, rather than policies focused on regulations and technology improvement. Our findings provide guidance for policy development by enabling the transfer of policy approaches among different states and regions.

The economic feasibility of Biomass District Heating (BDH) networks in rural villages is largely unknown. A cost-effective evaluation tool is developed to examine the feasibility of BDH in rural communities using secondary data sources. The approach is unique in that it accounts for all the major capital expenses: energy center, distribution network, and energy transfer stations, as well as biomass procurement. BDH would deliver heat below #2 fuel oil in eight of the ten rural study villages examined, saving nearly $500,000 per year in heating expenses while demanding less than 5% of the forest residues sustainably available regionally. Capital costs comprised over 80% of total costs, illuminating the importance of reaching a sufficient heat density. Reducing capital costs by 1% lowers total cost by $93,000 per year. Extending capital payment period length five years or lowering interest rates has the next highest influence decreasing delivered heat price 0.49% and 0.35% for each 1% change, respectively. This highlights that specific building heat is a strong determinant of feasibility given the relative influence of high-demanding users on the overall village heat-density. Finally, we use a stochastic analysis projecting future #2 fuel oil prices, incorporating historical variability, to determine the probability of future BDH feasibility. Although future oil prices drop below the BDH feasibility threshold, the villages retain a 22–53% probability of feasibility after 20 years as a result of high #2 fuel oil price variability.

Kneeling is an important function of the knee joint required for many daily activities. Bearing type is thought to influence functional outcome following UKA and TKA. Self-reported kneeling ability was recorded in 471 UKA and 206 TKA patients with fixed or mobile bearing implants. Kneeling ability was recorded from the Oxford Knee Score question 7. The self-reported ability to kneel was similar in patients with fixed and mobile bearing UKA implants following surgery. In TKA, greater proportions of patients were able to kneel in the fixed compared to the mobile bearing groups up to two years after surgery indicating that self-reported kneeling ability is enhanced in fixed compared to mobile bearing TKA.

When using a tournament in multi-period settings, firms have discretion in selecting the tournament horizon. For example, firms can use a single tournament (a grand tournament) or a sequence of multiple tournaments, each with a shorter horizon than a grand tournament (a repeated tournament). Firms have also begun to use a combination of both in which a repeated tournament is embedded within a grand tournament (a hybrid tournament). Using an experiment, we investigate whether the effect of tournament horizon on performance depends on the dynamic complexity of the task, which reflects the potential for effort in one period to influence the link between effort and performance in future periods. When dynamic task complexity is low, we find that performance is greatest in the hybrid tournament, followed by the repeated and then the grand tournament. In contrast, when dynamic task complexity is high, we find that performance is greatest in the repeated tournament, followed by the grand and hybrid tournaments, with similar performance in the latter two tournaments. More generally, the results of our experiment suggest that the effect of tournament horizon on performance depends on dynamic task complexity. These results can help firms make better decisions when designing their tournaments by reinforcing the need to align the tournament horizon with the task.

BACKGROUND: The six-minute walk test (6MWT) is a commonly used clinical assessment of exercise capacity in patients with cardiopulmonary or neuromuscular disease, but normal values are lacking for young adults, who are frequent subjects of testing. METHODS: In a two-center study, 272 young adults, ages 18–50, underwent American Thoracic Society protocolized six-minute walk testing, and 56 underwent repeat testing. A linear regression model was developed based on anthropomorphic data. This model was compared to existing prediction equations. RESULTS: Median 6MWD for the cohort was 637m (IQR 584 – 686m) and was not significantly impacted by age. This is in contrast to existing equations extrapolated from older subjects that predict increasing 6MWD in younger subjects. We found weak correlation of 6MWD with height, weight, BMI, and resting heart rate. Heart rate at completion correlated most strongly with 6MWD (rho 0.53 p

The activation of the bone morphogenic protein (BMP) signaling pathway in cancer cells has been shown to enhance migration and tumor angiogenesis and promote survival. The BMP signaling pathway regulates benign cells in the tumor microenvironment and is a known regulator of immune cells. The development of BMP receptor inhibitors has allowed the study of tumor xenografts in mice. We describe a double-humanized mouse model with adoptively transferred human immune and human tumor cells that can be used to assess the effects of BMP inhibitors on these human cells in vivo.

Interferon regulatory factor 2 binding protein-like (IRF2BPL) encodes a member of the IRF2BP family of transcriptional regulators. Currently the biological function of this gene is obscure, and the gene has not been associated with a Mendelian disease. Here we describe seven individuals who carry damaging heterozygous variants in IRF2BPL and are affected with neurological symptoms. Five individuals who carry IRF2BPL nonsense variants resulting in a premature stop codon display severe neurodevelopmental regression, hypotonia, progressive ataxia, seizures, and a lack of coordination. Two additional individuals, both with missense variants, display global developmental delay and seizures and a relatively milder phenotype than those with nonsense alleles. The IRF2BPL bioinformatics signature based on population genomics is consistent with a gene that is intolerant to variation. We show that the fruit-fly IRF2BPL ortholog, called pits (protein interacting with Ttk69 and Sin3A), is broadly detected, including in the nervous system. Complete loss of pits is lethal early in development, whereas partial knockdown with RNA interference in neurons leads to neurodegeneration, revealing a requirement for this gene in proper neuronal function and maintenance. The identified IRF2BPL nonsense variants behave as severe loss-of-function alleles in this model organism, and ectopic expression of the missense variants leads to a range of phenotypes. Taken together, our results show that IRF2BPL and pits are required in the nervous system in humans and flies, and their loss leads to a range of neurological phenotypes in both species.

Atypical dopamine uptake inhibitors (DUIs) bind to the dopamine transporter and inhibit the reuptake of dopamine but have lower abuse potential than psychostimulants. Several atypical DUIs can block abuse-related effects of cocaine and methamphetamine, thus making them potential medication candidates for psychostimulant use disorders. The aim of the current study is to establish an in-vivo assay using EEG for the rapid identification of atypical DUIs with potential for medication development. The typical DUIs cocaine and methylphenidate dose-dependently decreased the power of the alpha, beta, and gamma bands. The atypical DUI modafinil and its F-analog, JBG1-049, decreased the power of beta, but in contrast to cocaine, none of the other frequency bands, while JHW007 did not significantly alter the EEG spectrum. The mu-opioid receptor agonists heroin and morphine dose-dependently decreased the power of gamma and increased power of the other bands. The effect of morphine on EEG power bands was antagonized by naltrexone. The NMDA receptor antagonist ketamine increased the power of all frequency bands. Therefore, typical and atypical DUIs and drugs of other classes differentially affected EEG spectra, showing distinctive features in the magnitude and direction of their effects on EEG. Comparative analysis of the effects of test drugs on EEG indicates a potential atypical profile of JBG1-049 with similar potency and effectiveness to its parent compound modafinil. These data suggest that EEG can be used to rapidly screen compounds for potential activity at specific pharmacological targets and provide valuable information for guiding the early stages of drug development. This article is part of the issue entitled 'Special Issue on Neurotransmitter Transporters'.

The introduction discusses the impact of the discovery of the Dead Sea Scrolls on understanding the formation of scriptures in the Hellenistic-Roman period. Rather than focusing on the closure of the canon of the Hebrew Bible, this book assesses the processes by which texts become scripture. While the contemporary understanding of “liturgical” in Judaism and Christianity is related to formal fixed prayer, this study expands the concept of liturgical to include a range of practices around the study of sacred texts in Jewish antiquity. A traditioning process occurs through such practices of revelatory discernment in which scriptural interpretation is incorporated into texts which both sacralizes and extends them. The book’s methodological framework is rooted in embodied cognition and draws on insights from anthropology, ritual theory, memory studies, and neuroscience. A center of attention is the mediating role of the liturgical body in both an individual and corporate sense.

Chapter 3 considers the figure of Paul and the community in Corinth to argue that three practices in 2 Corinthians result in communal formation of the ecclesia and establish Paul as the authoritative apostolic author. The first is the collection for the saints in Jerusalem which reframes the Greco-Roman practice of euergatism. A second practice is the initial blessing of God which reconstrues the deep Judean memory of exile and restoration. Paul’s body can thus be understood as a “eucharistic body” in two senses. The community gives thanks as a corporate body to God as a result of the benefaction, and Paul’s body is the mediating instrument by which this thanksgiving is rendered. A third practice is the performance of the letter itself: subsequent readings by mediators both shape the community to which it is communicated and construct Paul as an author and revelatory authority because he is an exemplary sufferer like Christ.

Although by no means offering a complete taxonomy of scripture formation, the book considers a wide range of literary genres and practices across the diverse population of Judeans throughout the region. The conclusion draws out some of the implications for understanding the fluid nature of scriptures in the Hellenistic-Roman era. The search for the “original text” of the Bible is a vain one; rather, scriptures were formed through a traditioning process that involved sacralization through the entwinement of prayer practices and textual interpretation. These texts were mediated by learned teachers and leaders in textual communities.

While much scholarship has been concerned with the role of the scribal hand in the formation of texts, this chapter takes a new approach by assessing the scribal body of Ben Sira. The embodied actions of the scribal figure involve daily prayer which is understood to activate the spirit of wisdom and the ability to teach. Contemporary neurocognitive theory that understands the Self as a process helps to situate the scribe in relation to these practices of “lived religion.” Cultural values, especially honor and shame, also shape the scribal self in his larger communal engagement. The sage teaches his students to emulate his pious practices, to learn and augment wisdom, resulting in the expanding corpus of Sirach. The book of Sirach can thus be understood as the ongoing enactment of scribal teaching and training rather than the synchronic textual product of a single author.

Chapter 2 contrasts the role of the confessional prayers in Daniel 9 and Baruch 1:15–3:8 in relation to the Jeremiah tradition and textual production. Daniel receives revelatory visions in response to his prayer, but the confession plays no role in ending the exile. The narrative line of Baruch makes him the “first” to institutionalize confession as a practice, five years into the exile. The chapter argues that the ongoing practice of confession and the integration of scripturalized confessions in evolving textual traditions were decisive factors in how the text of what might be called “Jeremiah-Baruch” claimed authority for itself as scripture.

This chapter evaluates the Qumran Hodayot (Thanksgiving Hymns) in the manuscript 1QHa. Although the poems never entered anyone’s Bible, they nonetheless exhibit many of the dynamics seen in other texts that become scripture. Certain psalms within the collection are connected to the Maskil, the principal leader of the Yaḥad movement who claims possession of the divine spirit. The Maskil confesses esoteric knowledge reflecting a sectarian interpretation of scripture. The Maskil is called to prostrate himself like Moses, thus enacting an intercessory role for the community. The revelatory claims of the Maskil serve to sacralize the text. The youngest and most refined scroll of hodayot, 1QHa is scripture-like in the refined character of the manuscript. The intimate and intricate relationship between liturgy and scriptural interpretation, wisdom and prophecy, and their mediation by a leader cannot be separated from a consideration of the continuing performed enactment of the hodayot.

Older adults frequently experience depression and reduced well-being when transitioning to long-term care (LTC) that can lead to increased risk for mortality. In the current randomized controlled trial, older adults ( N = 93) who were transitioning to LTC facilities in Southeast Florida were enlisted. It was hypothesized that when transitioning to LTC (a) story sharing (i.e., sharing stories in groups) could lead to reduced depression and improved well-being, and (b) baseline sociodemographic characteristics could predict depression and well-being. Baseline results revealed that participants were not depressed and had moderate well-being, and postintervention results indicated that there were no significant improvements in depression ( p = 0.35) and well-being ( p = 0.41). Some baseline sociodemographic characteristics predicted depression ( p = 0.04) and well-being ( p = 0.03). Future research should incorporate moderate depression as an inclusion criterion and more weeks of story-sharing sessions. Targets: Adults age 65 and older transitioning to LTC. Intervention Description: Two to three participants met as a group to share five stories over 3 weeks. Mechanisms of Action: Story sharing will improve well-being. Outcomes: Participant level of well-being will improve, and sociodemographic characteristics and factors related to the move will predict risk for depression and reduced well-being. [Res Gerontol Nurs. 2019; 12(2):81–90.]

Protein S-sulfenylation, which results from oxidation of free thiols on cysteine residues, has recently emerged as an important post-translational modification that regulates the structure and function of proteins involved in a variety of physiological and pathological processes. By altering the size and physiochemical properties of modified cysteine residues, sulfenylation can impact the cellular function of proteins in several different ways. Thus, the ability to rapidly and accurately identify putative sulfenylation sites in proteins will provide important insights into redox-dependent regulation of protein function in a variety of cellular contexts. Though bottom-up proteomic approaches, such as tandem mass spectrometry (MS/MS), provide a wealth of information about global changes in the sulfenylation state of proteins, MS/MS-based experiments are often labor-intensive, costly and technically challenging. Therefore, to complement existing proteomic approaches, researchers have developed a series of computational tools to identify putative sulfenylation sites on proteins. However, existing methods often suffer from low accuracy, specificity, and/or sensitivity. In this study, we developed SVM-SulfoSite, a novel sulfenylation prediction tool that uses support vector machines (SVM) to identify key determinants of sulfenylation among five feature classes: binary code, physiochemical properties, k-space amino acid pairs, amino acid composition and high-quality physiochemical indices. Using 10-fold cross-validation, SVM-SulfoSite achieved 95% sensitivity and 83% specificity, with an overall accuracy of 89% and Matthew’s correlation coefficient (MCC) of 0.79. Likewise, using an independent test set of experimentally identified sulfenylation sites, our method achieved scores of 74%, 62%, 80% and 0.42 for accuracy, sensitivity, specificity and MCC, with an area under the receiver operator characteristic (ROC) curve of 0.81. Moreover, in side-by-side comparisons, SVM-SulfoSite performed as well as or better than existing sulfenylation prediction tools. Together, these results suggest that our method represents a robust and complementary technique for advanced exploration of protein S-sulfenylation.

We report the results of total ionizing dose (TID) and destructive and nondestructive single-event effects (SEE) testing of the Intersil ISL7059xSEH, 100μA and 1mA precision current sources.

Purpose Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. Methods In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing: A) Phenotyping; B) Reanalyses of FASTQ files, with innovative bioinformatics; C) Targeted molecular testing; D) Whole genome sequencing (WGS) and E) Conferring of clinical diagnoses when pathognomonic clinical findings occurred. Results Certain and Highly Likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping and targeted testing identifying variants that were undetected or not prioritized on prior ES. WGS diagnosed 3/18 individuals, with structural variants not amenable to ES. Additionally, Tentative diagnoses were made in three (8%) and in five individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). Conclusions Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without WGS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.