Search

Blockages of the ureter, e.g. due to calculi (kidney stones), can result in an increase in renal pelvic pressure. This may be relieved by inserting a stent (essentially a permeable hollow tube). However, a number of complications are associated with stent use. Stents can result in reflux (backflow of urine along the ureter), which will promote recurrent urinary infection and possible renal parenchymal damage. Furthermore, long-term stent use is associated with infection and precipitation of salts from the urine, which can lead to a build-up of crystalline deposits on the stent surface, making stent removal difficult and painful. This paper examines factors governing urine flow in a stented ureter, the implications for reflux, and the processes by which the stent surface encrusts, in particular focusing on the influence of bacterial infection. An interdisciplinary approach is adopted, involving a combination of theoretical investigations and novel experiments. [ABSTRACT FROM AUTHOR]

Caffeine (5 mg kg-1) was administered orally to two healthy, non- smoking subjects on three separate occasions-before, and during therapy with the xanthine oxidase inhibitor allopurinol at doses of either 300 or 600 mg daily. Plasma and urinary levels of methylxanthines, endogenous oxypurines and allopurinol and its metabolite oxypurinol were measured using h.p.l.c. analyses. Allopurinol treatment caused a specific, dose-dependent inhibition of the conversion of the caffeine metabolite 1-methylxanthine (1X) to 1- methyluric acid (1U). A good correlation was observed in both subjects between the urinary 1U/1X molar ratio and the ratio of endogenous urate to hypoxanthine + xanthine at the different allopurinol doses, supporting the proposal that the 1U/1X molar ratio after caffeine intake provides an in vivo index of xanthine oxidase activity in man. [ABSTRACT FROM AUTHOR]

A method is presented for the use of caffeine, in the forms commonly ingested by a large proportion of the world's population, to test for the clinically important acetylation polymorphism. Each of 146 subjects provided a spot sample of urine between 2 and 6 h after coffee, tea or cola soft drink consumption, and the molar ratio of 5-acetylamino-6- formylamino −3-methyluracil (AFMU) to 1-methylxanthine (1X) was determined by a simple h.p.l.c. assay. The ratio afforded segregation of three apparent modes of acetylation capacity in this population, in concordance with a standard sulphamethazine phenotyping procedure and with other methods using controlled caffeine intake and urine collections. The day-to-day consistency of the method was established in eight selected subjects. [ABSTRACT FROM AUTHOR]

Environmental DNA (eDNA) preserved in marine sediments is increasingly being used to study past ecosystems. However, little is known about how accurately marine biodiversity is recorded in sediment eDNA archives, especially planktonic taxa. Here, we address this question by comparing eukaryotic diversity in 273 eDNA samples from three water depths and the surface sediments of 24 stations in the Nordic Seas. Analysis of 18S-V9 metabarcoding data reveals distinct eukaryotic assemblages between water and sediment eDNA. Only 40% of Amplicon Sequence Variants (ASVs) detected in water were also found in sediment eDNA. Remarkably, the ASVs shared between water and sediment accounted for 80% of total sequence reads suggesting that a large amount of plankton DNA is transported to the seafloor, predominantly from abundant phytoplankton taxa. However, not all plankton taxa were equally archived on the seafloor. The plankton DNA deposited in the sediments was dominated by diatoms and showed an underrepresentation of certain nano- and picoplankton taxa (Picozoa or Prymnesiophyceae). Our study offers the first insights into the patterns of plankton diversity recorded in sediment in relation to seasonality and spatial variability of environmental conditions in the Nordic Seas. Our results suggest that the genetic composition and structure of the plankton community vary considerably throughout the water column and differ from what accumulates in the sediment. Hence, the interpretation of sedimentary eDNA archives should take into account potential taxonomic and abundance biases when reconstructing past changes in marine biodiversity., (© 2024 John Wiley & Sons Ltd.)

The culture-attenuated alcelaphine herpesvirus 1 (AlHV-1) C500 strain can be grown to high titre and has been used successfully as a candidate vaccine for wildebeest-associated malignant catarrhal fever (MCF). This vaccine virus was also used to develop an indirect ELISA to allow monitoring of virus-specific antibodies in vaccinated cattle. However the extraction method was expensive and time-consuming, and the resulting test was not suitable for use in sheep. Here we describe an improved antigen extraction method that also broadens the application of the assay, allowing its application to sheep samples. The updated assay was tested using control samples from cattle and sheep, and showed a high level of accuracy in both species. This novel assay should prove to be a useful tool in MCF diagnosis and in evaluation of MCF vaccine responses., Competing Interests: Declaration of Competing Interest I have nothing to declare, (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Crosstalk between mast cells (MCs) and T lymphocytes (TLs) releases specific signals that create an environment conducive to tumor development. Conversely, they can protect against cancer by targeting tumor cells for destruction. Although their role in immunity and cancer is complex, their potential in anticancer strategies is often underestimated. When peripheral MCs are activated, they can affect cancer development. Tumor-infiltrating TLs may malfunction and contribute to aggressive cancer and poor prognoses. One promising approach for cancer patients is TL-based immunotherapies. Recent reports suggest that MCs modulate TL activity in solid tumors and may be a potential therapeutic layer in multitargeting anticancer strategies. Pharmacologically modulating MC activity can enhance the anticancer cytotoxic TL response in tumors. By identifying tumor-specific targets, it has been possible to genetically alter patients' cells into fully humanized anticancer cellular therapies for autologous transplantation, including the engineering of TLs and MCs to target and kill cancer cells. Hence, recent scientific evidence provides a broader understanding of MC-TL activity in cancer., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Chagas disease is one of the most significant vector-borne diseases in Mexico. The presence of "sylvatic" triatomine vectors of Trypanosoma cruzi (Chagas) inside human dwellings necessitates estimating their vectorial capacity. To estimate this capacity in Triatoma protracta nahuatlae (Ryckman), Triatoma sinaloensis (Ryckman), and their laboratory hybrids, 6 biological parameters were examined. Triatoma sinaloensis exhibited the shortest development time (155 days), with a median of 12 blood meals. Mortality rates varied from 35% to 45% in the 3 studied cohorts. All 3 cohorts were aggressive, initiating feeding within 0.5-1 min, and had similar feeding periods ranging from 10 to 18 min. A majority (75.3-97.9%) of the hybrids defecated when feeding, immediately after feeding, or in less than 1 min post-feeding. In contrast, only 7-42% of nymphs of T. sinaloensis defecated during the same period. Our results regarding the 6 parameters studied confirm the potential role of T. p. nahuatlae as an efficient vector of T. cruzi. Triatoma sinaloensis, on the other hand, exhibited limited vectorial capacity primarily due to its poor defecation behavior. Continued surveillance of these "sylvatic" triatomine populations is necessary to prevent an epidemiological problem., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The role of parathyroid hormone (PTH)-related protein (PTHrP) in breast cancer remains controversial, with reports of PTHrP inhibiting or promoting primary tumor growth in preclinical studies. Here, we provide insight into these conflicting findings by assessing the role of specific biological domains of PTHrP in tumor progression through stable expression of PTHrP (-36-139aa) or truncated forms with deletion of the nuclear localization sequence (NLS) alone or in combination with the C-terminus. Although the full-length PTHrP molecule (-36-139aa) did not alter tumorigenesis, PTHrP lacking the NLS alone accelerated primary tumor growth by downregulating p27, while PTHrP lacking the NLS and C-terminus repressed tumor growth through p27 induction driven by the tumor suppressor leukemia inhibitory factor receptor (LIFR). Induction of p27 by PTHrP lacking the NLS and C-terminus persisted in bone disseminated cells, but did not prevent metastatic outgrowth, in contrast to the primary tumor site. These data suggest that the PTHrP NLS functions as a tumor suppressor, while the PTHrP C-terminus may act as an oncogenic switch to promote tumor progression through differential regulation of p27 signaling., (© 2024. The Author(s).)

Prolonged sedentary behaviour (SB) i.e. longer bouts, is suggested to have a range of negative health effects, independent of habitual light and medium-to-vigorous physical activity (LIPA or MVPA). Any effect on musculoskeletal size, architecture or morphology has seldom been reported in older adults. Moreover, no study has yet determined if any association would persist following adjustment for covariates. Therefore, the aim of the present study was to investigate the associations between SB, and properties of the Gastrocnemius Medialis (GM) muscle, in a cross-sectional sample of older adults using compositional data analysis. 105 healthy older adults (73±6y) wore a thigh mounted tri-axial accelerometer for seven consecutive days, and underwent ultrasound [e.g. muscle length (Lm), anatomical cross-sectional area (ACSA), muscle volume (VM), fascicle length (LF), & physiological cross-sectional area (PCSA)], body composition (e.g. DEXA) and health (e.g. medical history) assessments. In-unadjusted models, SB time was negatively associated with ACSA at 75% of Lm (R2adj = 0.085), VM (R2adj = 0.020), and PCSA (R2adj = 0.039). Standing was positively associated with pennation angle (R2adj = 0.110), which persisted following co-variate adjustment (R2adj = 0.296). In fully adjusted models, both SB & LIPA time were associated with ACSA at 75% of Lm (Both R2adj = 0.393). Standing and light activity time were also associated with LF, VM, & PCSA (R2adj 0.116-0.573). In fully adjusted models, SB pattern parameters (i.e. the manner in which sedentary behaviour is accumulated daily throughout waking hours such as the timing, duration and frequency of sedentary bouts), were associated with GM muscle properties (R2adj 0.156-0.564) including LM, LF, and VM. The pattern, rather than accumulated daily SB time, was associated with the size and architecture of the GM. Our results suggest that regardless of co-existing habitual physical activities, SB bouts should be kept short and frequently interrupted to offset some of the deleterious ageing-related muscle architecture characteristics changes., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Wullems et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Malignant catarrhal fever is a lymphoproliferative disease of cattle and other ungulates that is caused by genetically and antigenically related gamma herpesviruses of the genus Macavirus. Infection of the natural host species is efficient and asymptomatic but spread to susceptible hosts is often fatal with clinical signs including fever, depression, nasal and ocular discharge. There is no recognised treatment for MCF but a vaccine for one MCF virus, alcelaphine herpesvirus 1 (AlHV-1), has been described. In this paper we describe the inhibition of AlHV-1 replication and propagation by the anthelminthic drug ivermectin. Concentrations of 10 μM or greater led to significant reductions in both copy number and viable titre of virus tested in culture medium, with little replication detected at over 20 μM ivermectin. In the absence of alternative treatments, further testing of ivermectin as a candidate antiviral treatment for MCF may therefore be justified., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Osteochondral grafts are used for repair of focal osteochondral lesions. Autologous grafts are the gold standard treatment; however, limited graft availability and donor site morbidity restrict use. Therefore, there is a clinical need for different graft sources/materials which replicate natural cartilage function. Chitosan has been proposed for this application. The aim of this study was to assess the biomechanics and biotribology of a bioresorbable chitosan/chitosan-nano-hydroxyapatite osteochondral construct (OCC), implanted in an in vitro porcine knee experimental simulation model. The OCC implanted in different surgical positions (flush, proud and inverted) was compared to predicate grafts in current clinical use and a positive control consisting of a stainless steel graft implanted proud of the cartilage surface. After 3 h (10 800 cycles) wear simulation under a walking gait, subsidence occurred in all OCC samples irrespective of surgical positioning, but with no apparent loss of material and low meniscus wear. Half the predicate grafts exhibited delamination and scratching of the cartilage surfaces. No graft subsidence occurred in the positive controls but wear and deformation of the meniscus were apparent. Implanting a new chitosan-based OCC either optimally (flush), inverted or proud of the cartilage surface resulted in minimal wear, damage and deformation of the meniscus., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

PARP7 is a member of the ADP-ribosyltransferase diphtheria toxin-like (ARTD) family and acts as a repressor of type I interferon (IFN) signaling. PARP7 inhibition causes tumor regression by enhancing antitumor immunity, which is dependent on the stimulator of interferon genes (STING) pathway, TANK-binding kinase 1 (TBK1) activity, and cytotoxic CD8 + T cells. To better understand PARP7's role in cancer, we generated and characterized PARP7 knockout (Parp7 KO ) EO771 mouse mammary cancer cells in vitro and in a preclinical syngeneic tumor model using catalytic mutant Parp7 H532A mice. Loss of PARP7 expression or inhibition of its activity increased type I IFN signaling, as well as the levels of interferon-stimulated gene factor 3 (ISGF3) and specifically unphosphorylated-ISGF3 regulated target genes. This was partly because PARP7's modification of the RelA subunit of nuclear factor κ-B (NF-κB). PARP7 loss had no effect on tumor growth in immunodeficient mice. In contrast, injection of wildtype cells into Parp7 H532A mice resulted in smaller tumors compared with cells injected into Parp7 +/+ mice. Parp7 H532A mice injected with Parp7 KO cells failed to develop tumors and those that developed regressed. Our data highlight the importance of PARP7 in the immune cells and further support targeting PARP7 for anticancer therapy.

Echinococcus multilocularis ( Em ), the causative agent of human alveolar echinococcosis (AE), is present in the Holarctic region, and several genetic variants deem to have differential infectivity and pathogenicity. An unprecedented outbreak of human AE cases in Western Canada infected with a European-like strain circulating in wild hosts warranted assessment of whether this strain was derived from a recent invasion or was endemic but undetected. Using nuclear and mitochondrial markers, we investigated the genetic diversity of Em in wild coyotes and red foxes from Western Canada, compared the genetic variants identified to global isolates and assessed their spatial distribution to infer possible invasion dynamics. Genetic variants from Western Canada were closely related to the original European clade, with lesser genetic diversity than that expected for a long-established strain and spatial genetic discontinuities within the study area, supporting the hypothesis of a relatively recent invasion with various founder events.

The aryl hydrocarbon receptor (AHR), a transcription factor best known for mediating toxic responses of environmental pollutants, also integrates metabolic signals to promote anti-inflammatory responses, intestinal homeostasis, and maintain barrier integrity. AHR regulates its target genes through direct DNA-binding to aryl hydrocarbon response elements (AHREs) but also through tethering to other transcription factors in a DNA-binding independent manner. However, it is not known if AHR's anti-inflammatory role in the gut requires its ability to bind to AHREs. To test this, we determined the sensitivity of Ahrdbd/dbd mice, a genetically modified mouse line that express an AHR protein incapable of binding to AHREs, to dextran sulfate sodium (DSS)-induced colitis. Ahrdbd/dbd mice exhibited more severe symptoms of intestinal inflammation than Ahr+/+ mice. None of the Ahrdbd/dbd mice survived after the 5-day DSS followed by 7-day washout period. By day 6, the Ahrdbd/dbd mice had severe body weight loss, shortening of the colon, higher disease index scores, enlarged spleens, and increased expression of several inflammation genes, including interleukin 1b (Il-1b), Il-6, Il-17, C-x-c motif chemokine ligand 1 (Cxcl1), Cxcl2, Prostaglandin-endoperoxide synthase (Ptgs2), and lipocalin-2. Our findings show that AHR's DNA-binding domain and ability to bind to AHREs are required to reduce inflammation, maintain a healthy intestinal environment, and protect against DSS-induced colitis., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society of Toxicology.)

Research has documented neurophysiological indicators of anticipation (Stimulus Preceding Negativity [SPN]) and perception (Late Positive Potential [LPP]) of threat, yet little is known as to how self-focused attention manipulations influence emotion processing within the context of cued picture viewing. With self-referent attention moderating attention to external stimuli, it is necessary to document how self-focused attention impacts attention and the ability to emotionally process external threat. The goal of the present study was to evaluate the impact of self-focused attention on the anticipation and perceptual processing of unpleasant pictures within a cued-picture viewing paradigm among 33 participants. Overall, the results suggest that the self-focused attention manipulations disrupted anticipation but not processing of pictures, as indexed by the SPN and LPP respectively. Self-focused attention appears to disrupt the preparatory attention for upcoming unpleasant stimuli, potentially through loading cognitive resources or activation of associative defensive responding. Collectively, these findings demonstrate the impact of self-focused attention within the context of emotional picture processing and suggest further areas of investigation., (© 2022. The Psychonomic Society, Inc.)

The mono-ADP-ribosyltransferase PARP7 has emerged as a key negative regulator of cytosolic NA-sensors of the innate immune system. We apply a rational design strategy for converting a pan-PARP inhibitor into a potent selective PARP7 inhibitor (KMR-206). Consistent with studies using the structurally distinct PARP7 inhibitor RBN-2397, co-treatment of mouse embryonic fibroblasts with KMR-206 and NA-sensor ligands synergistically induced the expression of the type I interferon, IFN-β. In mouse colon carcinoma (CT-26) cells, KMR-206 alone induced IFN-β. Both KMR-206 and RBN-2397 increased PARP7 protein levels in CT-26 cells, demonstrating that PARP7's catalytic activity regulates its own protein levels. Curiously, treatment with saturating doses of KMR-206 and RBN-2397 achieved different levels of PARP7 protein, which correlated with the magnitude of type I interferon gene expression. These latter results have important implications for the mechanism of action of PARP7 inhibitors and highlights the usefulness of having structurally distinct chemical probes for the same target., Competing Interests: Declaration of interests M.S.C, D.J.S, K.M.R, and S.S are co-inventors on a provisional patent describing the inhibitors in this study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Radiation to the carotid arteries, e.g. in the context of head and neck cancer treatment, is one of several risk factors for artery stenosis. In principle, this fact may also have implications for stereotactic cervical spine radiotherapy, because long-term survival can be achieved in patients with oligometastatic disease and favorable prognostic features. Here, we suggest that radiation dose distributions with reduced dose to the carotid artery are achievable when planning stereotactic cervical spine radiotherapy. Patients with high likelihood of long-term survival may benefit from such vessel-sparing approaches., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

The Social Anxiety Questionnaire (SAQ) is a 10-item measure of social anxiety developed to comprehensively and concisely target the mechanisms described in Clark and Wells' model of social anxiety and address the breadth of social anxiety symptoms which may not all be encompassed in existing questionnaires. The aim of the current studies is to independently investigate the factor structure of the SAQ (i.e., Study 1 and 2) and determine its predictive validity and utility (i.e., Study 3 and 4). Data were collected across 4 studies to evaluate the factor structure and utility. Overall, the results suggest that a total summed score of the SAQ appeared to capture unique aspects of social anxiety that may not be captured using a single measure and appears to provide utility in experimental manipulations of theoretical maintenance factors. The current study was limited by a convenience sample and future research should continue to document the psychometric properties and clinical utility of this novel measure of social anxiety. The SAQ may show promise in both correlational and experimental research but future research should consider further evaluation of its utility., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

An innovative approach was developed to engineer a multi-layered chitosan scaffold for osteochondral defect repair. A combination of freeze drying and porogen-leaching out methods produced a porous, bioresorbable scaffold with a distinct gradient of pore size (mean = 160-275 μm). Incorporation of 70 wt% nano-hydroxyapatite (nHA) provided additional strength to the bone-like layer. The scaffold showed instantaneous mechanical recovery under compressive loading and did not delaminate under tensile loading. The scaffold supported the attachment and proliferation of human mesenchymal stem cells (MSCs), with typical adherent cell morphology found on the bone layer compared to a rounded cell morphology on the chondrogenic layer. Osteogenic and chondrogenic differentiation of MSCs preferentially occurred in selected layers of the scaffold in vitro, driven by the distinct pore gradient and material composition. This scaffold is a suitable candidate for minimally invasive arthroscopic delivery in the clinic with potential to regenerate damaged cartilage and bone., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Models of social anxiety propose that negative self-imagery is a maintenance factor of psychopathology, yet the mechanisms of this relationship are unclear. One proposed mechanism is attention towards self-images. However, self-image creation does not occur in isolation and is likely influenced by other mechanisms, such as anticipatory processing (AP). The current study aimed to investigate how trait social anxiety and AP influence motivated attention during self-imagery (i.e., late-positive potential; LPP). Participants (N = 40) with a mean age of 18.95 (SD = 1.22) completed AP manipulations and a self-imagery task. Results revealed that participants with high levels of social anxiety who engaged in AP demonstrated blunted LPP activity in the late time window (6000-10,000 ms) relative to those who engaged in Distraction. These results suggest that motivated attention towards self-imagery may be impacted by anticipatory processing, but less influenced by the valence of self-imagery. Given previous research has been limited in methodology, this study expands upon current research by documenting the neural mechanisms of self-imagery manipulations within social anxiety., (Copyright © 2022. Published by Elsevier B.V.)

Poly-ADP-ribose polymerases (PARPs) are important regulators of the immune system, including TCDD-inducible poly-ADP-ribose polymerase (TIPARP), also known as poly-ADP-ribose polymerase 7 (PARP7). PARP7 negatively regulates aryl hydrocarbon receptor (AHR) and type I interferon (IFN-I) signaling, both of which have been implicated in intestinal homeostasis and immunity. Since the loss of PARP7 expression increases AHR and IFN-I signaling, we used a murine dextran sulfate sodium (DSS)-induced colitis model to investigate the effect of PARP7 loss on DSS-induced intestinal inflammation. DSS-exposed Parp7 -/- mice had less body weight loss, lower disease index scores, and reduced expression of several inflammation genes, including interleukin IL-6 , C-x-c motif chemokine ligand 1 ( Cxcl1 ), and lipocalin-2, when compared with wild-type mice. However, no significant difference was observed between genotypes in the colonic expression of the AHR target gene cytochrome P450 1A1 ( Cyp1a1 ). Moreover, no significant differences in microbial composition were observed between the genotypes. Our findings demonstrate that the absence of PARP7 protein results in an impaired immune response to colonic inflammation and suggests that PARP7 may participate in the recruitment of immune cells to the inflammation site, which may be due to its role in IFN-I signaling rather than AHR signaling.

The minor capsid protein of ovine herpesvirus 2, identified as a potential antigen for serological testing, was over-expressed and purified to allow its assessment in ELISA. The corresponding gene sequence (OvHV-2 orf65, Ov65) was modified to incorporate epitope tags and internal restriction enzyme sites in an E. coli codon-optimised version of the gene. This codon-optimised gene was then subject to internal deletions to identify regions of the protein that could be removed while maintaining protein solubility and antigenicity. It was found that a derivative with deletion of the conserved 5'-end of the gene (Ov65delB) expressed a polypeptide that was soluble when over-expressed in bacteria and was detected by OvHV-2 specific sera. Proteomic analysis of the affinity purified Ov65delB showed that it contained multiple predicted Ov65 tryptic peptides but also showed contamination by co-purifying E. coli proteins. An indirect ELISA, based on this affinity-purified OV65delB, was optimised for use with sheep and cattle samples and cut-off values were established based on known negative serum samples. Analysis of groups of samples that were either presumed infected (UK sheep) or tested OvHV-2 positive or negative by PCR (cattle MCF diagnostic samples) showed that the assay had 95 % sensitivity and 96 % specificity for sheep serum; and 80 % sensitivity and 95 % specificity for cattle serum. The lower sensitivity with cattle samples appeared to be due to a lack of serological response in some MCF-affected cattle. This recombinant antigen therefore shows promise as the basis of an inexpensive, simple and reliable test that can be used to detect OvHV-2-specific antibody responses in both MCF-affected animals and in OvHV-2 reservoir hosts., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

Chagas disease is a very important vector-borne disease in México, and Triatoma dimidiata sensu stricto (Latreille) is one of the most important vectors of Trypanosoma cruzi Chagas, mainly in southern and central states. In the Pacific Coast states with the highest prevalence of human T. cruzi infection, T. dimidiata s. s. is considered as a secondary vector. However, the vectorial capacity of those populations has not been studied. Therefore, the vector characteristics of three populations of T. dimidiata s. s. in western México were evaluated in this study. The populations were maintained in the laboratory at 27 ± 1°C and 75% ± 5% RH with a 12:12 h (light:dark) regime, fed on rabbits in a fortnight basis. The development times were short (172-238 d), and the number of bloodmeals to molt was low (11). Mortality was moderate (36-45%), the onset of feeding was relatively rapid (0.5-1.7 min), and feedings were extended (>15 min). More than 40% of individuals in most instars defecated in one of three categories: <1 min when feeding (5-37.9%), immediately after feeding (9-28.6%), or in <1 min post feeding (7-25.8%). The median number of laid eggs was high (over 2.5) in the three populations, as were the egg eclosion rates (>86%). Thus, the T. dimidiata s. s. in the three populations are potentially efficient vectors of T. cruzi and could contribute to the high prevalence of infection in human populations in western México., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America.All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Research attempting to identify pathways from childhood maltreatment to adulthood posttraumatic stress symptoms (PTSS) implicates cognitive vulnerabilities that may increase risk for mental health concerns. The present study examined two cognitive vulnerabilities and their relation to PTSS amongst individuals with and without childhood maltreatment histories: attentional control and repetitive negative thinking (RNT). This research surveyed college students ( N  = 376) on constructs of interest. Results revealed that attentional control and RNT demonstrated significant indirect effects on PTSS ( 95% CI =.0003, .0336 and 95% CI =.0643, .1857, respectively). Findings suggest that childhood maltreatment severity was related to decreased attentional control and increased RNT, which were then both related to increased PTSS. Interventions for increasing attentional control and decreasing RNT should be implemented and evaluated for young adults with early adversity currently experiencing PTSS.

2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible poly-adenosine diphosphate (ADP)-ribose polymerase (TIPARP/PARP7), an aryl hydrocarbon receptor (AHR) target gene and mono-ADP-ribosyltransferase, acts as part of a negative feedback loop to repress AHR signaling. This process is prevented by a single H532A mutation in TIPARP that destroys its catalytic activity. We hypothesized that the loss of TIPARP catalytic activity would increase sensitivity to TCDD-induced toxicity in vivo. To test this, we created a catalytically deficient mouse line (TiparpH532A) by introducing a single H532A mutation in TIPARP. Treatment of mouse embryonic fibroblasts or hepatocytes isolated from TiparpH532A mice confirmed the increased TCDD-induced expression of the AHR target genes Cyp1a1, Cyp1b1, and Tiparp. TiparpH532A mice given a single injection of 10 µg/kg TCDD, a nonlethal dose in Tiparp+/+ mice, did not survive beyond day 10. All Tiparp+/+ mice survived the 30-day treatment. TCDD-treated TiparpH532A mice displayed increased expression of AHR target genes, increased steatohepatitis and hepatotoxicity. Hepatic RNA-sequencing revealed 7-fold more differentially expressed genes in TiparpH532A mice than in Tiparp+/+ mice (4542 vs 647 genes) 6 days after TCDD treatment. Differentially expressed genes included genes involved in xenobiotic metabolism, lipid homeostasis and inflammation. Taken together, these data further support TIPARP as a critical negative regulator of AHR activity and show that loss of its catalytic activity is sufficient to increase sensitivity to TCDD-induced steatohepatitis and lethality. Since TIPARP inhibition has recently emerged as a potential anticancer therapy, the impact on AHR signaling, TCDD and polycyclic aromatic hydrocarbon toxicity will need to be carefully considered under conditions of therapeutic TIPARP inhibition., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Society of Toxicology.)

Phosphate-based glasses (PBGs) are biomaterials that degrade under physiological conditions and can be modified to release various ions depending on end applications. This study utilized slow-degrading (P45:45P 2 O 5 -16CaO-24MgO-11Na 2 O-4Fe 2 O 3 , mol %) and comparatively faster degrading (P40:40P 2 O 5 -16CaO-24MgO-20Na 2 O, mol %) PBG microspheres with or without porosity, to evaluate the combined effect of chemical formulation and geometry on human mesenchymal stem cells (MSCs), a clinically relevant cell source for orthopedic applications. Scanning electron microscopy showed 2, 46, and 29% of P45 bulk (P45-B), P40 bulk (P40-B), and P40 porous (P40-P) microspheres, respectively, that had cracks or peeling off surfaces after 42 days of incubation in culture medium. Cytotoxicity assessment showed that glass debris released into the culture medium may interact with cells and affect their survival. Direct-contact cell experiments up to 42 days showed that P45-B microspheres did not sustain viable long-term cell cultures and did not facilitate extracellular matrix formation. On the other hand, P40-B microspheres enhanced alkaline phosphatase activity, calcium deposition, and collagen and osteocalcin production in MSCs. Introduction of porosity in P40 glass further enhanced these parameters and proliferation at later time points. The small pore windows (<5 μm wide) and interconnection (<10 μm wide) may have allowed limited cell penetration into the porous structures. P40-B and P40-P have potential for bone repair and reinforcement therapy based on their chemical formulation and porous geometry.

Ag/Ga were incorporated into resorbable orthopaedic phosphate bioactive glasses (PBG, containing P, Ca, Mg, Na, and Fe) thin films to demonstrate their potential to limit growth of Staphylococcus aureus and Escherichia coli in post-operative prosthetic implantation. Dual target consecutive co-sputtering was uniquely employed to produce a 46 nm Ag:PBG composite observed by high resolution TEM to consist of uniformly dispersed ~5 nm metallic Ag nano-particles in a glass matrix. Ga 3+ was integrated into a phosphate glass preform target which was magnetron sputtered to film thicknesses of ~400 or 1400 nm. All coatings exhibited high surface energy of 75.4-77.3 mN/m, attributed to the presence of hydrolytic P-O-P structural surface bonds. Degradation profiles obtained in deionized water, nutrient broth and cell culture medium showed varying ion release profiles, whereby Ga release was measured in 1400 nm coating by ICP-MS to be ~6, 27, and 4 ppm respectively, fully dissolving by 24 h. Solubility of Ag nanoparticles was only observed in nutrient broth (~9 ppm by 24 h). Quantification of colony forming units after 24 h showed encouraging antibacterial efficacy towards both S. aureus (4-log reduction for Ag:PBG and 6-log reduction for Ga-PBG≈1400 nm) and E. coli (5-log reduction for all physical vapour deposited layers) strains. Human Hs27 fibroblast and mesenchymal stem cell line in vitro tests indicated good cytocompatibility for all sputtered layers, with a marginal cell proliferation inertia in the case of the Ag:PBG composite thin film. The study therefore highlights the ( i ) significant manufacturing development via the controlled inclusion of metallic nanoparticles into a PBG glass matrix by dual consecutive target co-sputtering and ( ii ) potential of PBG resorbable thin-film structures to incorporate and release cytocompatible/antibacterial oxides. Both architectures showed prospective bio-functional performance for a future generation of endo-osseous implant-type coatings., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

Objective: Data indicate that adverse childhood experiences (ACEs) are a risk factor for cognitive and attentional vulnerabilities. A vulnerability linked to these impairments is repetitive negative thinking (RNT), and data suggest that RNT and anxiety symptoms may be moderated by attentional control. The current study investigated the effect of these risk factors on symptoms of anxiety. Participants: College students ( N  = 376) were recruited from a university. Methods: Participants were administered questionnaires online to assess retrospective ACEs, current RNT, attentional control, and anxiety symptoms. Results: There was an indirect effect of ACEs on anxiety symptoms through RNT. High attentional control moderated the indirect effects, such that high compared to low attentional control was associated with an increased effect of RNT on anxiety symptoms. Conclusions: Increased ACEs may be a risk factor for RNT among college students. Combined with high attentional control, these may be risk factors for anxiety symptoms.

Objective: Social anxiety and depression are commonly comorbid and cause significant impairment in college students. Past research suggests that both poor attentional control and increased rumination are related to these disorders and independently mediate their relationship. Theory suggests that social anxiety loads working memory, thus decreasing attentional control, which influences rumination and depression. The current study aimed to investigate the potential combined influence of attention control and rumination on social anxiety and depression. Participants: Participants (80) were recruited from a large Midwestern university in September 2017. Methods: Participants completed questionnaires regarding social anxiety, attentional control, rumination, and depression and data were analyzed using bias-corrected bootstrapping analyses. Results: Results demonstrate a significant indirect relationship between social anxiety and depression through attentional control and rumination. Conclusions: Results indicated that college students with social anxiety may be at risk for depression due to decreased attentional control and increased rumination. Clinical implications are discussed.

The experimental vaccine for bovine malignant catarrhal fever consists of viable attenuated alcelaphine herpesvirus 1 (AlHV-1) derived by extensive culture passage, combined with an oil-in-water adjuvant, delivered intramuscularly. This immunisation strategy was over 80% effective in previous experimental and field trials and protection appeared to be associated with induction of virus-neutralising antibodies. Whether the vaccine virus is required to be viable at the point of immunisation and whether adjuvant is required to induce the appropriate immune responses remains unclear. To address these issues two studies were performed, firstly to analyse immune responses in the presence and absence of adjuvant and secondly, to investigate immune responses to vaccines containing adjuvant plus viable or inactivated AlHV-1. The first study showed that viable attenuated AlHV-1 in the absence of adjuvant induced virus-specific antibodies but the titres of virus-neutralising antibodies were significantly lower than those induced by vaccine containing viable virus and adjuvant, suggesting adjuvant was required for optimal responses. In contrast, the second study found that the vaccine containing inactivated (>99.9%) AlHV-1 induced similar levels of virus-neutralising antibody to the equivalent formulation containing viable AlHV-1. Together these studies suggest that the MCF vaccine acts as an antigen depot for induction of immune responses, requiring adjuvant and a suitable antigen source, which need not be viable virus. These observations may help in directing the development of alternative MCF vaccine formulations for distribution in the absence of an extensive cold chain., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Authors.)

ADP-ribosylation is a post-translational protein modification catalyzed by a family of proteins known as poly-ADP-ribose polymerases. PARP7 (TIPARP; ARTD14) is a mono-ADP-ribosyltransferase involved in several cellular processes, including responses to hypoxia, innate immunity and regulation of nuclear receptors. Since previous studies suggested that PARP7 was regulated by 17β-estradiol, we investigated whether PARP7 regulates estrogen receptor α signaling. We confirmed the 17β-estradiol-dependent increases of PARP7 mRNA and protein levels in MCF-7 cells, and observed recruitment of estrogen receptor α to the promoter of PARP7. Overexpression of PARP7 decreased ligand-dependent estrogen receptor α signaling, while treatment of PARP7 knockout MCF-7 cells with 17β-estradiol resulted in increased expression of and recruitment to estrogen receptor α target genes, in addition to increased proliferation. Co-immunoprecipitation assays revealed that PARP7 mono-ADP-ribosylated estrogen receptor α, and mass spectrometry mapped the modified peptides to the receptor's ligand-independent transactivation domain. Co-immunoprecipitation with truncated estrogen receptor α variants identified that the hinge region of the receptor is required for PARP7-dependent mono-ADP-ribosylation. These results imply that PARP7-mediated mono-ADP-ribosylation may play an important role in estrogen receptor positive breast cancer.

Poly(ADP-ribose) polymerase 7 (PARP-7) has emerged as a critically important member of a large enzyme family that catalyzes ADP-ribosylation in mammalian cells. PARP-7 is a critical regulator of the innate immune response. What remains unclear is the mechanism by which PARP-7 regulates this process, namely because the protein targets of PARP-7 mono-ADP-ribosylation (MARylation) are largely unknown. Here, we combine chemical genetics, proximity labeling, and proteome-wide amino acid ADP-ribosylation site profiling for identifying the direct targets and sites of PARP-7-mediated MARylation in a cellular context. We found that the inactive PARP family member, PARP-13-a critical regulator of the antiviral innate immune response-is a major target of PARP-7. PARP-13 is preferentially MARylated on cysteine residues in its RNA binding zinc finger domain. Proteome-wide ADP-ribosylation analysis reveals cysteine as a major MARylation acceptor of PARP-7. This study provides insight into PARP-7 targeting and MARylation site preference., Competing Interests: KR, SB, IK, IS, DH, MR, DG, LD, JM, MN, MC No competing interests declared, (© 2021, Rodriguez et al.)

NAD + is a critical molecule that is involved in multiple cellular functions. CD38 is a multifunctional enzyme with NAD + nucleosidase activity. Our previous work revealed the CD38-dependent interactions of isoniazid (INH), an antituberculosis drug, with NAD + to form INH-NAD adduct. In the current work, our metabolomic analysis discovered a novel NAD + adduct with acetylisoniazid (AcINH), a primary INH metabolite mediated by N -acetyltransferase (NAT), and we named it AcINH-NAD. Using Nat1/2(-/-) and Cd38(-/-) mice, we determined that AcINH-NAD formation is dependent on both NAT and CD38. Because NAT is expressed in hepatocytes (HP), whereas CD38 is expressed in Kupffer cells (KC) and hepatic stellate cells (HSC), we explored cell type-specific roles of CD38 in the formation of AcINH-NAD as well as INH-NAD. We found that both INH-NAD and AcINH-NAD were produced in the incubation of INH or AcINH with KC and HSC but not in HP. These data suggest that hepatic nonparenchymal cells, such as KC and HSC, are the major cell types responsible for the CD38-dependent interactions of INH with NAD + in the liver. SIGNIFICANCE STATEMENT: The current study identified AcINH-NAD as a novel metabolite of INH in the liver. Our work also revealed the essential roles of nonparenchymal cells, including Kupffer cells and hepatic stellate cells, in the CD38-dependent interactions of NAD + with INH, leading to the formation of both INH-NAD and AcINH-NAD in the liver. These data can be used to guide the future studies on the mechanisms of INH and NAD + interactions and their contributions to INH-induced liver injury., (Copyright © 2020 by The American Society for Pharmacology and Experimental Therapeutics.)

Investigations of fear conditioning have recently begun to evaluate contextual factors that affect attention-related processes. However, much of the extant literature does not evaluate how contextual fear learning influences neural indicators of attentional processes during goal-directed activity. The current study evaluated how early attention for task-relevant stimuli and conflict monitoring were affected when presented within task-irrelevant safety and threat contexts after fear learning. Participants (N = 72) completed a Flanker task with modified context before and after context-dependent fear learning. Flanker stimuli were presented in the same threat and safety contexts utilized in the fear learning task while EEG was collected. Results indicated increased early attention (N1) to flankers appearing in threat contexts and later increased neural indicators (P2) of attention to flankers appearing in safety contexts. Results of this study indicate that contextual fear learning modulates early attentional processes for task-relevant stimuli that appear in the context of safety and threat. Theoretical and clinical implications are discussed.

Liver cancer is the third most common cause of cancer-related death but is almost 4-fold more prevalent in men than in women. Increased risk in men may be due in part to elevated chronic inflammation, which is a crucial driving force for many cancers. Male mice also have a greater incidence of liver cancer than females after postnatal exposure to procarcinogens such as 4-aminobiphenyl (ABP) or diethylnitrosamine (DEN), or in mice that transgenically express hepatitis B virus (HBV) proteins. Liver damage, inflammation and proliferation are central to liver cancer development, and previous studies have shown that hepatocellular damage, inflammation and proliferation are acutely elevated to a greater extent in adult male mice than in females after high-dose exposure to DEN. In contrast, postnatal exposure of mice to tumor-inducing doses of either DEN or ABP produces no such acute responses. However, it is not known whether sex differences in responses to postnatal carcinogen exposure or to HBV protein expression may develop over time following sexual maturation. We conducted an extended time course study to compare markers of liver damage, inflammation and proliferation between male and female mice exposed postnatally to 600 nmol ABP or 10 mg/kg DEN, and also in HBV transgenic (HBVTg) mice, over the duration of time that mice are normally maintained for standard liver tumor development protocols. Postnatal exposure to either ABP or DEN produced no evidence of either acute or chronic hepatocyte damage, liver inflammation or proliferation in either male or female mice. In contrast, HBVTg mice showed increased liver damage, inflammation and proliferation with age, but with no observed sex difference. These findings suggest that although chronic liver damage, inflammation and proliferation may be drivers for liver cancer development, they are unlikely to contribute directly to observed sex differences in liver tumor risk., (Copyright © 2020 Elsevier B.V. All rights reserved.)

There is an increasing number of shared decision-making (SDM) interventions in paediatrics. However, there is little consensus as to the best instruments to assess the feasibility and impact of these interventions. This narrative review aims to answer: (1) what feasibility, knowledge and decision-making instruments have been used to assess paediatric SDM interventions and (2) what are the psychometric properties of used decision-making instruments, guided by the 'consensus-based standards for the selection of health measurement instrument' criteria. We conducted a review of the peer-reviewed literature. We identified 23 studies that evaluated a paediatric intervention to facilitate SDM for a specific health decision. Eighteen studies assessed intervention feasibility, with a wide variability in assessment between studies. Twelve studies assessed objective knowledge, and four studies assessed subjective knowledge with all but one study aggregating correct responses. We identified nine decision-making instruments that had been assessed psychometrically, although few had been thoroughly evaluated. The Decisional Conflict Scale was the most commonly-used instrument and the only instrument evaluated in paediatrics. Our study revealed a lack of consistency in the instruments used to evaluate decision-making interventions in paediatrics, making it difficult to compare interventions. We provide several recommendations for researchers to improve the assessment of SDM interventions in paediatrics.

Attentional control has grown in importance within theoretical and predictive models of psychopathology over past decades. The Attentional Style Questionnaire (ASQ) is a novel measure of internal and external attentional control. However, no study has independently validated this questionnaire. Two studies assessed the factor structure for the ASQ within an English-speaking population (Study 1), evaluated the construct and content validity, and assessed incremental predictability (Study 2). Results of Study 1 observed two factors that could be characterised as distractibility/cognitive avoidance and focusing, whereas the original study had observed factors defined as internal and external. Results of Study 2 confirmed the factor structure of Study 1, in addition to providing evidence for the ASQ's predictability for anxiety, depression and worry behaviours above established measures of attentional control. Overall, these results indicated that the ASQ measures factors of attentional control which provides incremental utility for predicting psychopathology. Implications on psychopathology and discrepancies to previous findings are discussed.

Titanate structures have been widely investigated as biomedical component surfaces due to their bioactive, osteoinductive and antibacterial properties. However, these surfaces are limited to Ti and its alloys, due to the nature of the chemical conversion employed. The authors present a new method for generating nanoporous titanate structures on alternative biomaterial surfaces, such as other metals/alloys, ceramics and polymers, to produce bioactive and/or antibacterial properties in a simple yet effective way. Wet chemical (NaOH; 5 M; 60 °C; 24 h) conversion of DC magnetron sputtered Ti surfaces on 316L stainless steel were investigated to explore effects of microstructure on sodium titanate conversion. It was found that the more equiaxed thin films (B/300) generated the thickest titanate structures (ca. 1.6 μm), which disagreed with the proposed hypothesis of columnar structures allowing greater NaOH ingress. All film parameters tested ultimately generated titanate structures, as confirmed via EDX, SEM, XPS, XRD, FTIR and Raman analyses. Additionally, the more columnar structures (NB/NH & B/NH) had a greater quantity of Na (ca. 26 at.%) in the top portion of the films, as confirmed via XPS, however, on average the Na content was consistent across the films (ca. 5-9 at.%). Film adhesion for the more columnar structures (ca. 42 MPa), even on polished substrates, were close to that of the FDA requirement for plasma-sprayed HA coatings (ca. 50 MPa). This study demonstrates the potential of these surfaces to be applied onto a wide variety of material types, even polymeric materials, due to the lower processing temperatures utilised, with the vision to generate bioactive and/or antibacterial properties on a plethora of bioinert materials., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.)

A major challenge in orthopedics is the repair of large non-union bone fractures. A promising therapy for this indication is the use of biodegradable bioinspired biomaterials that stabilize the fracture site, relieve pain and initiate bone formation and healing. This study uses a multidisciplinary evaluation strategy to assess immunogenicity, allergenicity, bone responses and physicochemical properties of a novel biomaterial scaffold. Two-photon stereolithography generated personalized custom-built scaffolds with a repeating 3D structure of Schwarz Primitive minimal surface unit cell with a specific pore size of ∼400 μm from three different methacrylated poly(d,l-lactide-co-ε-caprolactone) copolymers with lactide to caprolactone monomer ratios of 16 : 4, 18 : 2 and 9 : 1. Using in vitro and in vivo assays for bone responses, immunological reactions and degradation dynamics, we found that copolymer composition influenced the scaffold physicochemical and biological properties. The scaffolds with the fastest degradation rate correlated with adverse cellular effects and mechanical stiffness correlated with in vitro osteoblast mineralization. The physicochemical properties also correlated with in vivo bone healing and immune responses. Overall these observations provide compelling support for these scaffolds for bone repair and illustrate the effectiveness of a promising multidisciplinary strategy with great potential for the preclinical evaluation of biomaterials.

Preimplantation equine embryos synthesize and secrete fibrinogen, which is a peculiar finding as fibrinogen synthesis almost exclusively occurs in the liver. This study investigated the hypothesis that conceptus-derived fibrinogen mediates cell adhesion during fixation. On day 21 of pregnancy, five integrin subunits, including ITGA5, ITGB1, ITGAV, and ITGB1, displayed significantly higher transcript abundance than on day 16 of pregnancy. Endometrial epithelial cells adhered to fibrinogen in an integrin-dependent manner in an in vitro cell adhesion assay. Bilaminar trophoblast and allantochorion expressed fibrinogen transcript, indicating that fibrinogen expression persists past fixation. Preimplantation-phase endometrium, conceptuses, and microcotyledonary tissue expressed components of the clotting cascade regulating fibrin homeostasis, leaving open the possibility that fibrinogen is converted to fibrin. Fibrinogen is likely to have functions beyond mediating cell adhesion, such trapping growth factors and triggering signaling cascades, and has remarkable parallels to the expression of fibrinogen by some tumors. The deposition of fibrinogen within tumor stroma is characteristic of breast carcinoma, and tumor-derived fibrinogen has been implicated in the metastatic potential of circulating tumor cells. DNA methylation of the fibrinogen locus in equine conceptuses was examined in comparison to liver and endometrium, and across the full gene cluster, was significantly higher for endometrium than liver and conceptus. DNA methylation of regulatory regions did not differ between liver and conceptus, and was significantly lower than in endometrium. These results, therefore, support the hypothesis of DNA methylation being a regulator of fibrinogen expression in the conceptus., (© The Author(s) 2019. Published by Oxford University Press on behalf of Society for the Study of Reproduction. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

An open question in the metal hydride community is whether there are simple, physics-based design rules that dictate the thermodynamic properties of these materials across the variety of structures and chemistry they can exhibit. While black box machine learning-based algorithms can predict these properties with some success, they do not directly provide the basis on which these predictions are made, therefore complicating the a priori design of novel materials exhibiting a desired property value. In this work we demonstrate how feature importance, as identified by a gradient boosting tree regressor, uncovers the strong dependence of the metal hydride equilibrium H 2 pressure on a volume-based descriptor that can be computed from just the elemental composition of the intermetallic alloy. Elucidation of this simple structure-property relationship is valid across a range of compositions, metal substitutions, and structural classes exhibited by intermetallic hydrides. This permits rational targeting of novel intermetallics for high-pressure hydrogen storage (low-stability hydrides) by their descriptor values, and we predict a known intermetallic to form a low-stability hydride (as confirmed by density functional theory calculations) that has not yet been experimentally investigated.

Aromatic amines are an important class of human carcinogens found ubiquitously in our environment. It is estimated that 1 in 8 of all known or suspected human carcinogens is or can be converted into an aromatic amine, making the elucidation of their mechanisms of toxicity a top public health priority. Decades of research into aromatic amine carcinogenesis revealed a complex bioactivation process where Phase I and Phase II drug metabolizing enzymes catalyze N-oxidation and subsequent conjugation reactions generating the highly electrophilic nitrenium intermediate that reacts with and forms adducts on cellular macromolecules. Although aromatic amine-DNA adducts were believed to be the main driver of cancer formation, several studies have reported a lack of correlation between levels of DNA adducts and tumors. Using genetically modified mouse models, our laboratory and others observed several instances where levels of conventionally measured DNA adducts failed to correlate with liver tumor incidence following exposure to the model aromatic amine procarcinogen 4-aminobiphenyl. In this review we first provide a historical overview of the studies that led to a proposed mechanism of carcinogenesis caused by aromatic amines, where their bioactivation to form DNA adducts represents the central driver of this process. We then highlight recent mechanistic studies using 4-aminobiphenyl that are inconsistent with this mechanism which suggest novel drivers of aromatic amine carcinogenesis., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The emotional cascade model proposes that the emotional instability and engagement in maladaptive behaviors within borderline personality disorder (BPD) may be linked to rumination. Previous research has established that BPD is highly related to neuroticism, childhood emotional vulnerability, and parental invalidation. Therefore, the purpose of the current study was to assess whether the constructs of the emotional cascade model relate to other constructs within the BPD nomological network. More specifically, neuroticism, childhood emotional vulnerability, and parental invalidation should relate to the ruminative process and engagement in maladaptive behaviors as described by the emotional cascade model. The current study investigated the relation between these factors using a cross-lagged panel design with data collected online at 3 time points in a student sample and an Amazon Mechanical Turk sample. Neuroticism predicted rumination 1 month later across both samples and for 3 measures of rumination. Childhood emotional vulnerability and parental invalidation predicted rumination 2 months later for 2 measures of rumination in the student sample only. Future studies should continue to investigate the potential role of personality traits and BPD vulnerability factors within the emotional cascade model. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

TCDD-inducible poly-ADP-ribose polymerase (TIPARP) is an aryl hydrocarbon receptor (AHR) target gene that functions as part of a negative feedback loop to repress AHR activity. Tiparp -/- mice exhibit increased sensitivity to the toxicological effects of 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD), including lethal wasting syndrome. However, it is not known whether Tiparp -/- mice also exhibit increased sensitivity to other AHR ligands. In this study, we treated male Tiparp -/- or wild type (WT) mice with a single injection of 100 mg/kg 3-methylcholanthrene (3MC). Consistent with TIPARP's role as a repressor of AHR signaling, 3MC-treated Tiparp -/- mice exhibited increased hepatic Cyp1a1 and Cyp1b1 levels compared with WT mice. No 3MC-treated Tiparp -/- mice survived beyond day 16 and the mice exhibited chylous ascites characterized by an accumulation of fluid in the peritoneal cavity. All WT mice survived the 30-day treatment and showed no signs of fluid accumulation. Treated Tiparp -/- mice also exhibited a transient and mild hepatotoxicity with inflammation. 3MC-treated WT, but not Tiparp -/- mice, developed mild hepatic steatosis. Lipid deposits accumulated on the surface of the liver and other abdominal organs in the 3MC- Tiparp -/- mice. Our study reveals that Tiparp -/- mice have increased sensitivity to 3MC-induced liver toxicity, but unlike with TCDD, lethality is due to chylous ascites rather than wasting syndrome.

Social anxiety disorder (SAD) and major depressive disorder (MDD) are comorbid conditions, and SAD confers risk for MDD. Biased attention and interpersonal rejection are important for the development of SAD and MDD, but little research has examined how these processes may lead to MDD. We hypothesized that interpersonal rejection would result in SAD symptoms being associated with more "depression-like" attention biases. Participants (n = 164) completed a measure of SAD symptoms and an eye tracking task before and after a task in which they were randomized to be socially included or rejected. SAD symptoms, inclusion or rejection condition, and the interaction term were entered into separate hierarchical linear regressions predicting change in attention for five emotional faces. Rejection condition significantly moderated the effects of SAD on change in attention to sad, happy, and neutral faces. SAD predicted increased attention to sad faces and decreased attention to happy faces in the rejection condition, but not in the inclusion condition. SAD predicted increased attention to neutral faces in the inclusion condition, but not in the rejection condition. There were no significant effects for angry or disgust. Results suggest that SAD symptoms are associated with more depression-like attention biases in the context of interpersonal rejection., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Phosphate-based glasses (PBGs) are bioactive and fully degradable materials with tailorable degradation rates. PBGs can be produced as porous microspheres through a single-step process, using changes in their formulation and geometry to produce varying pore sizes and interconnectivity for use in a range of applications, including biomedical use. Calcium phosphate PBGs have recently been proposed as orthobiologics, based on their in vitro cytocompatibility and ion release profile. In this study, porous microspheres made of two PBG formulations either containing TiO 2 (P40Ti) or without (P40) were implanted in vivo in a large animal model of bone defect. The biocompatibility and osteogenic potential of these porous materials were assessed 13 weeks postimplantation in sheep and compared to empty defects and autologous bone grafts used as negative and positive controls. Histological analysis showed marked differences between the two formulations, as lower trabeculae-like interconnection and higher fatty bone marrow content were observed in the faster degrading P40-implanted defects, while the slower degrading P40Ti material promoted dense interconnected tissue. Autologous bone marrow concentrate (BMC) was also incorporated within the P40 and P40Ti microspheres in some defects; however, no significant differences were observed in comparison to microspheres implanted alone. Both formulations induced the formation of a collagen-enriched matrix, from 20 to 40% for P40 and P40Ti2.5 groups, suggesting commitment toward the bone lineage. With the faster degrading P40 formulation, mineralization of the tissue matrix was observed both with and without BMC. Some lymphocyte-like cells and foreign body multinucleated giant cells were observed with P40Ti2.5, suggesting that this more durable formulation might be linked to an inflammatory response. In conclusion, these first in vivo results indicate that PBG microspheres could be useful candidates for bone repair and regenerative medicine strategies and highlight the role of material degradation in the process of tissue formation and maturation.

Recent studies have revealed a possible link between the activities of polymorphic arylamine N-acetyltransferases (NATs) and energy metabolism. We used a Nat1/Nat2 double knockout (KO) mouse model to demonstrate that ablation of the two Nat genes is associated with modest, intermittent alterations in respiratory exchange rate. Pyruvate tolerance tests show that double KO mice have attenuated hepatic gluconeogenesis when maintained on a high-fat/high-sucrose diet. Absence of the two Nat genes also leads to an increase in the hepatic concentration of coenzyme A in mice fed a high-fat/high-sucrose diet. Our results suggest a modest involvement of NAT in energy metabolism in mice, which is consistent with the absence of major phenotypic deregulation of energy metabolism in slow human acetylators., (© 2019 Federation of European Biochemical Societies.)

High social anxiety is associated with increased attentional bias, and difficulties disengaging from relevant threat information, though social anxiety may also be associated with avoidance of threat. Few mechanisms of this relationship have been empirically evaluated, whereas theories and treatment manuals implicate avoidance and/or safety behaviors as significant agents of negative reinforcement for anxiety symptoms and search for threat. The current study sought to investigate one safety behavior, excessive reassurance seeking, as a mediator of the relationship between social anxiety and attention bias to disgust facial stimuli. Support was found for our hypotheses, such that social anxiety symptoms had an indirect effect on attention bias to disgust faces through increased reassurance seeking. These results suggest that reassurance seeking may result in disengagement of attention to threat stimuli. Specifically, social anxiety may result in a decreased threshold for negative social cues and therefore seek out reassurance feedback and avoid threatening stimuli. Future studies should test these directly and utilize a prospective design. The current study suggests that reassurance seeking may be involved in the attention bias process, providing additional data for current cognitive theories of social anxiety and additional support for reinforcement patterns of anxiety symptoms., (Copyright © 2019 Elsevier B.V. All rights reserved.)