Nasal bots carry relevant titers of CWD prions in naturally infected white-tailed deer.

Chronic wasting disease (CWD) is a prion disease affecting farmed and free-ranging cervids. CWD is rapidly expanding across North America and its mechanisms of transmission are not completely understood. Considering that cervids are commonly afflicted by nasal bot flies, we tested the potential of these parasites to transmit CWD. Parasites collected from naturally infected white-tailed deer were evaluated for their prion content using the protein misfolding cyclic amplification (PMCA) technology and bioassays. Here, we describe PMCA seeding activity in nasal bot larvae collected from naturally infected, nonclinical deer. These parasites efficiently infect CWD-susceptible mice in ways suggestive of high infectivity titers. To further mimic environmental transmission, bot larvae homogenates were mixed with soils, and plants were grown on them. We show that both soils and plants exposed to CWD-infected bot homogenates displayed seeding activity by PMCA. This is the first report describing prion infectivity in a naturally occurring deer parasite. Our data also demonstrate that CWD prions contained in nasal bots interact with environmental components and may be relevant for disease transmission.

Constitutive nuclear accumulation of endogenous alpha-synuclein in mice causes motor impairment and cortical dysfunction, independent of protein aggregation.

A growing body of evidence suggests that nuclear alpha-synuclein (αSyn) plays a role in the pathogenesis of Parkinson's disease (PD). However, this question has been difficult to address as controlling the localization of αSyn in experimental systems often requires protein overexpression, which affects its aggregation propensity. To overcome this, we engineered SncaNLS mice, which localize endogenous αSyn to the nucleus. We characterized these mice on a behavioral, histological and biochemical level to determine whether the increase of nuclear αSyn is sufficient to elicit PD-like phenotypes. SncaNLS mice exhibit age-dependent motor deficits and altered gastrointestinal function. We found that these phenotypes were not linked to αSyn aggregation or phosphorylation. Through histological analyses, we observed motor cortex atrophy in the absence of midbrain dopaminergic neurodegeneration. We sampled cortical proteomes of SncaNLS mice and controls to determine the molecular underpinnings of these pathologies. Interestingly, we found several dysregulated proteins involved in dopaminergic signaling, including Darpp32, Pde10a and Gng7, which we further confirmed was decreased in cortical samples of the SncaNLS mice compared with controls. These results suggest that chronic endogenous nuclear αSyn can elicit toxic phenotypes in mice, independent of its aggregation. This model raises key questions related to the mechanism of αSyn toxicity in PD and provides a new model to study an underappreciated aspect of PD pathogenesis.

The Current Status and Use of Microphysiological Systems by the Pharmaceutical Industry: The International Consortium for Innovation and Quality Microphysiological Systems Affiliate Survey and Commentary.

Microphysiological systems (MPS) are comprised of one or multiple cell types of human or animal origins that mimic the biochemical/electrical/mechanical responses and blood-tissue barrier properties of the cells observed within a complex organ. The goal of incorporating these in vitro systems is to expedite and advance the drug discovery and development paradigm with improved predictive and translational capabilities. Considering the industry need for improved efficiency and the broad challenges of model qualification and acceptance, the International Consortium for Innovation and Quality (IQ) founded an IQ MPS working group in 2014 and Affiliate in 2018. This group connects thought leaders and end users, provides a forum for crosspharma collaboration, and engages with regulators to qualify translationally relevant MPS models. To understand how pharmaceutical companies are using MPS, the IQ MPS Affiliate conducted two surveys in 2019, survey 1, and 2021, survey 2, which differed slightly in the scope of definition of the complex in vitro models under question. The surveys captured demographics, resourcing, rank order for organs of interest, compound modalities tested, and MPS organ-specific questions, including nonclinical species needs and cell types. The major focus of this manuscript is on results from survey 2, where we specifically highlight the context of use for MPS within safety, pharmacology, or absorption, disposition, metabolism, and excretion and discuss considerations for including MPS data in regulatory submissions. In summary, these data provide valuable insights for developers, regulators, and pharma, offering a view into current industry practices and future considerations while highlighting key challenges impacting MPS adoption. SIGNIFICANCE STATEMENT: The application of microphysiological systems (MPS) represents a growing area of interest in the drug discovery and development framework. This study surveyed 20+ pharma companies to understand resourcing, current areas of application, and the key challenges and barriers to internal MPS adoption. These results will provide regulators, tech providers, and pharma industry leaders a starting point to assess the current state of MPS applications along with key learnings to effectively realize the potential of MPS as an emerging technology.

Characterization of the complete mitochondrial genomes of the zoonotic parasites Bolbosoma nipponicum and Corynosoma villosum (Acanthocephala: Polymorphida) and the molecular phylogeny of the order Polymorphida.

Acanthocephalans of the order Polymorphida mainly parasitic in birds and mammals, are of veterinary, medical and economic importance. However, the evolutionary relationships of its 3 families (Centrorhynchidae, Polymorphidae and Plagiorhynchidae) remain under debate. Additionally, some species of Polymorphida (i.e. Bolbosoma spp. and Corynosoma spp.) are recognized as zoonotic parasites, associated with human acanthocephaliasis, but the mitochondrial genomes for representatives of Bolbosoma and Corynosoma have not been reported so far. In the present study, the complete mitochondrial genomes B. nipponicum and C. villosum (Acanthocephala: Polymorphidae) are reported for the first time, which are 14 296 and 14 241 bp in length, respectively, and both contain 36 genes [including 12 PCGs, 22 tRNA genes and 2 rRNA genes] and 2 non-coding regions (NCR1 and NCR2). The gene arrangement of some tRNAs in the mitogenomes of B. nipponicum and C. villosum differs from that found in all other acanthocephalans, except Polymorphus minutus. Phylogenetic results based on concatenated amino acid (AA) sequences of the 12 protein-coding genes (PCGs) strongly supported that the family Polymorphidae is a sister to the Centrorhynchidae rather than the Plagiorhynchidae, and also confirmed the sister relationship of the genera Bolbosoma and Corynosoma in the Polymorphidae based on the mitogenomic data for the first time. Our present findings further clarified the phylogenetic relationships of the 3 families Plagiorhynchidae, Centrorhynchidae and Polymorphidae, enriched the mitogenome data of the phylum Acanthocephala (especially the order Polymorphida), and provided the resource of genetic data for diagnosing these 2 pathogenic parasites of human acanthocephaliasis.

Urinary MicroRNA Biomarkers of Nephrotoxicity in Macaca fascicularis.

Drug-induced kidney injury (DIKI) refers to kidney damage resulting from the administration of medications. The aim of this project was to identify reliable urinary microRNA (miRNAs) biomarkers that can be used as potential predictors of DIKI before disease diagnosis. This study quantified a panel of six miRNAs (miRs-210-3p, 423-5p, 143-3p, 130b-3p, 486-5p, 193a-3p) across multiple time points using urinary samples from a previous investigation evaluating effects of a nephrotoxicant in cynomolgus monkeys. Exosome-associated miRNA exhibited distinctive trends when compared to miRNAs quantified in whole urine, which may reflect a different urinary excretion mechanism of miRNAs than those released passively into the urine. Although further research and mechanistic studies are required to elucidate how these miRNAs regulate signaling in disease pathways, we present, for the first time, data that several miRNAs displayed strong correlations with histopathology scores, thus indicating their potential use as biomarkers to predict the development of DIKI in preclinical studies and clinical trials. Also, these findings can potentially be translated into other non-clinical species or human for the detection of DIKI.

Variation in ecological scorecards and their potential for wider use.

Ecological monitoring is a vital tool to help us assess habitat condition and understand the mechanism(s) for habitat change. Yet many countries struggle to meet their monitoring requirements in part due to the high assessment workload. Rapid ecological assessment methods may have an important role to play in this regard. Following their success within several European habitats (e.g., semi-natural grasslands), they are now being developed for additional habitats such as heathlands, peatlands, and other agri-associated areas. Whilst some rapid assessments using ecological scorecards have been shown to be accurate compared to traditional ecological monitoring, less is known about the functionality of these scorecards in heterogenous landscapes. In this study, we selected four existing scorecards to test alongside a prototype. We assessed how these different scorecards measured habitat condition on the same heathland sites. We found that the choice of metrics, their score weighting, and the thresholds used for categorical scores cause scorecards to assess the same site with substantial variation (37%). Vegetation metrics were the primary cause of score variation, with vegetation structure and positive indicator species being the leading causes. Our study indicates that whilst current scorecards may be representative of project-specific goals, they may not be suitable for wider monitoring uses in their current form. Ecological scorecards have great potential to drastically increase the extent of monitoring, but caution is needed before adapting existing scorecards beyond the purposes from which they were designed.

Endothelial Cell Calcium Influx Mediates Trauma-induced Endothelial Permeability.

OBJECTIVE: We aimed to investigate if ex vivo plasma from injured patients causes endothelial calcium (Ca2+) influx as a mechanism of trauma-induced endothelial permeability. SUMMARY BACKGROUND DATA: Endothelial permeability after trauma contributes to post-injury organ dysfunction. While the mechanisms remain unclear, emerging evidence suggests intracellular Ca2+ signaling may play a role. METHODS: Ex vivo plasma from injured patients with "Low Injury/Low Shock" (injury severity score [ISS]<15, base excess [BE])≥-6mEq/L) and "High Injury/High Shock" (ISS≥15, BE<-6mEq/L) were used to treat endothelial cells. Experimental conditions included Ca2+ removal from the extracellular buffer, cyclopiazonic acid pre-treatment to deplete intracellular Ca2+ stores, and GSK2193874 pre-treatment to block the TRPV4 Ca2+ channel. Live cell fluorescence microscopy and ECIS were used to assess cytosolic Ca2+ increases and permeability, respectively. Western blot and live cell actin staining were used to assess myosin light chain (MLC) phosphorylation and actomyosin contraction. RESULTS: Compared to Low Injury/Low Shock plasma, High Injury/High Shock induced greater cytosolic Ca2+ increase. Cytosolic Ca2+ increase, MLC phosphorylation, and actin cytoskeletal contraction were lower without extracellular Ca2+ present. High Injury/High Shock plasma did not induce endothelial permeability without extracellular Ca2+ present. TRPV4 inhibition lowered trauma plasma-induced endothelial Ca2+ influx and permeability. CONCLUSIONS: This study illuminates a novel mechanism of post-injury endotheliopathy involving Ca2+ influx via the TRPV4 channel. TRPV4 inhibition mitigates trauma-induced endothelial permeability. Moreover, widespread endothelial Ca2+ influx may contribute to trauma-induced hypocalcemia. This study provides the mechanistic basis for the development of Ca2+-targeted therapies and interventions in the care of severely injured patients.

An Interactive Database for the Assessment of Histone Antibody Specificity.

Access to high-quality antibodies is a necessity for the study of histones and their posttranslational modifications (PTMs). Here we debut the Histone Antibody Specificity Database (http://www.histoneantibodies.com), an online and expanding resource cataloging the behavior of widely used, commercially available histone antibodies by peptide microarray. This interactive web portal provides a critical resource to the biological research community that routinely uses these antibodies as detection reagents for a wide range of applications.

Prodromal Dementia With Lewy Bodies: Evolution of Symptoms and Predictors of Dementia Onset.

BACKGROUND: Research criteria for prodromal dementia with Lewy bodies (DLB) were published in 2020, but little is known regarding prodromal DLB in clinical settings. METHODS: We identified non-demented participants without neurodegenerative disease from the National Alzheimer's Coordinating Center Uniform Data Set who converted to DLB at a subsequent visit. Prevalence of neuropsychiatric and motor symptoms were examined up to 5 years prior to DLB diagnosis. RESULTS: The sample included 116 participants clinically diagnosed with DLB and 348 age and sex-matched (1:3) Healthy Controls. Motor slowing was present in approximately 70% of participants 3 years prior to DLB diagnosis. In the prodromal phase, 50% of DLB participants demonstrated gait disorder, 70% had rigidity, 20% endorsed visual hallucinations, and over 50% of participants endorsed REM sleep behavior disorder. Apathy, depression, and anxiety were common prodromal neuropsychiatric symptoms. The presence of 1+ core clinical features of DLB in combination with apathy, depression, or anxiety resulted in the greatest AUC (0.815; 95% CI: 0.767, 0.865) for distinguishing HC from prodromal DLB 1 year prior to diagnosis. The presence of 2+ core clinical features was also accurate in differentiating between groups (AUC = 0.806; 95% CI: 0.756, 0.855). CONCLUSION: A wide range of motor, neuropsychiatric and other core clinical symptoms are common in prodromal DLB. A combination of core clinical features, neuropsychiatric symptoms and cognitive impairment can accurately differentiate DLB from normal aging prior to dementia onset.

Dendritic Cell Maturation Defines Immunological Responsiveness of Tumors to Radiation Therapy.

Radiation therapy is capable of directing adaptive immune responses against tumors by stimulating the release of endogenous adjuvants and tumor-associated Ags. Within the tumor, conventional type 1 dendritic cells (cDC1s) are uniquely positioned to respond to these signals, uptake exogenous tumor Ags, and migrate to the tumor draining lymph node to initiate cross-priming of tumor-reactive cytotoxic CD8+ T cells. In this study, we report that radiation therapy promotes the activation of intratumoral cDC1s in radioimmunogenic murine tumors, and this process fails to occur in poorly radioimmunogenic murine tumors. In poorly radioimmunogenic tumors, the adjuvant polyinosinic-polycytidylic acid overcomes this failure following radiation and successfully drives intratumoral cDC1 maturation, ultimately resulting in durable tumor cures. Depletion studies revealed that both cDC1 and CD8+ T cells are required for tumor regression following combination therapy. We further demonstrate that treatment with radiation and polyinosinic-polycytidylic acid significantly expands the proportion of proliferating CD8+ T cells in the tumor with enhanced cytolytic potential and requires T cell migration from lymph nodes for therapeutic efficacy. Thus, we conclude that lack of endogenous adjuvant release or active suppression following radiation therapy may limit its efficacy in poorly radioimmunogenic tumors, and coadministration of exogenous adjuvants that promote cDC1 maturation and migration can overcome this limitation to improve tumor control following radiation therapy.

Molecular basis for enantioselective herbicide degradation imparted by aryloxyalkanoate dioxygenases in transgenic plants.

The synthetic auxin 2,4-dichlorophenoxyacetic acid (2,4-D) is an active ingredient of thousands of commercial herbicides. Multiple species of bacteria degrade 2,4-D via a pathway initiated by the Fe(II) and α-ketoglutarate (Fe/αKG)-dependent aryloxyalkanoate dioxygenases (AADs). Recently, genes encoding 2 AADs have been deployed commercially in herbicide-tolerant crops. Some AADs can also inactivate chiral phenoxypropionate and aryloxyphenoxypropionate (AOPP) herbicides, albeit with varying substrate enantioselectivities. Certain AAD enzymes, such as AAD-1, have expanded utility in weed control systems by enabling the use of diverse modes of action with a single trait. Here, we report 1) the use of a genomic context-based approach to identify 59 additional members of the AAD class, 2) the biochemical characterization of AAD-2 from Bradyrhizobium diazoefficiens USDA 110 as a catalyst to degrade (S)-stereoisomers of chiral synthetic auxins and AOPP herbicides, 3) spectroscopic data that demonstrate the canonical ferryl complex in the AAD-1 reaction, and 4) crystal structures of representatives of the AAD class. Structures of AAD-1, an (R)-enantiomer substrate-specific enzyme, in complexes with a phenoxypropionate synthetic auxin or with AOPP herbicides and of AAD-2, which has the opposite (S)-enantiomeric substrate specificity, reveal the structural basis for stereoselectivity and provide insights into a common catalytic mechanism.

Disaster Risk Planning With Fuzzy Goal Programming.

The uncertainty in the timing and severity of disaster events makes the long-term planning of mitigation and recovery actions both critical and extremely difficult. Planners often use expected values for hazard occurrences, leaving communities vulnerable to worse-than-usual and even so-called "black swan" events. This research models disasters in terms of their best-case, most-likely, and worst-case damage estimates. These values are then embedded in a fuzzy goal programming model to provide community planners and stakeholders with the ability to strategize for any range of events from best-case to worst-case by adjusting goal weights. Examples are given illustrating the modeling approach, and an analysis is provided to illustrate how planners might use the model as a planning tool.

Omics Markers of Red Blood Cell Transfusion in Trauma.

Red blood cell (RBC) transfusion is a life-saving intervention for millions of trauma patients every year worldwide. While hemoglobin thresholds are clinically driving the need for RBC transfusion, limited information is available with respect to transfusion efficacy at the molecular level in clinically relevant cohorts. Here, we combined plasma metabolomic and proteomic measurements in longitudinal samples (n = 118; up to 13 time points; total samples: 690) from trauma patients enrolled in the control of major bleeding after trauma (COMBAT) study. Samples were collected in the emergency department and at continuous intervals up to 168 h (seven days) post-hospitalization. Statistical analyses were performed to determine omics correlate to transfusions of one, two, three, five, or more packed RBC units. While confounded by the concomitant transfusion of other blood components and other iatrogenic interventions (e.g., surgery), here we report that transfusion of one or more packed RBCs­mostly occurring within the first 4 h from hospitalization in this cohort­results in the increase in circulating levels of additive solution components (e.g., mannitol, phosphate) and decreases in the levels of circulating markers of hypoxia, such as lactate, carboxylic acids (e.g., succinate), sphingosine 1-phosphate, polyamines (especially spermidine), and hypoxanthine metabolites with potential roles in thromboinflammatory modulation after trauma. These correlations were the strongest in patients with the highest new injury severity scores (NISS > 25) and lowest base excess (BE < −10), and the effect observed was proportional to the number of units transfused. We thus show that transfusion of packed RBCs transiently increases the circulating levels of plasticizers­likely leaching from the blood units during refrigerated storage in the blood bank. Changes in the levels of arginine metabolites (especially citrulline to ornithine ratios) are indicative of an effect of transfusion on nitric oxide metabolism, which could potentially contribute to endothelial regulation. RBC transfusion was associated with changes in the circulating levels of coagulation factors, fibrinogen chains, and RBC-proteins. Changes in lysophospholipids and acyl-carnitines were observed upon transfusion, suggestive of an effect on the circulating lipidome­though cell-extrinsic/intrinsic effects and/or the contribution of other blood components cannot be disentangled. By showing a significant decrease in circulating markers of hypoxia, this study provides the first multi-omics characterization of RBC transfusion efficacy in a clinically relevant cohort of trauma patients.

Early-phenotype CAR-T cells for the treatment of pediatric cancers.

Chimeric antigen receptor (CAR)-T-cell therapy is a promising approach for the treatment of childhood cancers, particularly high-risk tumors that fail to respond to standard therapies. CAR-T cells have been highly successful in treating some types of hematological malignancies. However, CAR-T cells targeting solid cancers have had limited success so far for multiple reasons, including their poor long-term persistence and proliferation. Evidence is emerging to show that maintaining CAR-T cells in an early, less-differentiated state in vitro results in superior persistence, proliferation, and antitumor effects in vivo. Children are ideal candidates for receiving less-differentiated CAR-T cells, because their peripheral T-cell pool primarily comprises naïve cells that could readily be harvested in large numbers to generate early-phenotype CAR-T cells. Although several studies have reported different approaches to successfully generate early CAR-T cells, there are only a few clinical trials testing these in adult patients. No trials are currently testing early CAR-T cells in children. Here, we summarize the different strategies used to maintain CAR-T cells in an early phenotypic stage and present evidence suggesting that this approach may be particularly relevant to treating childhood cancers.

Review of metazoan parasites of the northern fur seal (Callorhinus ursinus) and the analysis of the gastrointestinal helminth community of the population on St. Paul Island, Alaska.

The northern fur seal (NFS), Callorhinus ursinus (Mammalia: Otariidae), is a marine mammal species included into the IUCN Red List as the vulnerable species which population is dramatically declining. A significant amount of parasitological data collected previously and our recent data allowed us to clarify the list of NFS metazoan parasites and to perform a comprehensive analysis of the gastrointestinal helminth community. Gastrointestinal tracts from 756 NFSs (3- to 4-year-old males) were collected during the annual Aleut subsistence harvests in July-August of 2011-2014 from five separate rookeries on St. Paul Island, Alaska. Totally, 27,625 specimens of helminths and approximately 1000 nasal mites were collected and identified. Detailed analysis of the previously published and newly obtained data revealed 32 species of metazoan parasites, including trematodes (6 species), cestodes (4), nematodes (9), acanthocephalans (9) and arthropods (4). The gastrointestinal helminth community of newly studied NFSs comprised 19 species including trematodes (4), cestodes (3), nematodes (5) and acanthocephalans (7). Temporal changes in the helminth community structure were small but statistically significant. Gastrointestinal helminth infracommunities comprised from 1 to 10 species (average of 4). Small but significant correlation was found between the abundances of acanthocephalans (Corynosoma similis and C. strumosum), nematodes (Contracaecum osculatum, Pseudoterranova spp.) and cestode Diphyllobothrium tetrapterum.

Combined use of splinted labial lithium disilicate veneers and a bonded nickel-chromium alloy palatal splint for tooth stabilization: A clinical report with 4-year follow-up.

This clinical report describes the restoration of severely compromised maxillary teeth in a 20-year-old woman secondary to excessive root shortening and minimal bone support but surrounded by healthy and esthetic soft tissues. The maxillary bone volume precluded provision of an implant-supported fixed or removable dental prosthesis without extensive grafting procedures. Splinted labial lithium disilicate veneers and a bonded nickel-chromium alloy palatal splint were used to stabilize and retain the structurally compromised maxillary teeth. At the 4-year review, the splinted veneers remained intact.

Comparison of Corrosion Products From Implant and Various Gold-Based Abutment Couplings: The Effect of Gold Plating.

This study compared titanium (Ti), palladium (Pd), platinum (Pt), and gold (Au) ion release following induced accelerated tribocorrosion from three Au alloy abutment groups coupled with Ti implants over time; investigated contacting surface structural changes; and explored the effect of Au plating. Three abutment groups, G (n = 8, GoldAdapt, Nobel Biocare), N (n = 8, cast UCLA, Biomet3i), and P (n = 8, cast UCLA, Biomet3i, Au plated), coupled with implants (Nobel Biocare), immersed in 1% lactic acid, were cyclically loaded. Ions released (ppb) at T1, T2, and T3, simulating 3, 5, and 12 months of function, respectively, were quantified by inductively coupled plasma mass spectrometry (ICP-MS) and compared. Surface degradation and fretted particle composition after T3 were evaluated with scanning electron microscopy and energy-dispersive X-ray spectroscopy (SEM/EDX). ICP-MS data were nonparametric, expressed as medians and interquartile ranges. SEM/EDX showed pitting, crevice corrosion, and fretted particles on the components. Released ion concentrations in all groups across time significantly decreased for Pd (P < .001, median range: 1.70-0.09), Pt (P = .021, 0.55-0.00), and Au (P < .001, 1.01-0.00) and increased for Ti (P = .018, 2.49-5.84). Total Ti release was greater than other ions combined for G (P = .012, 9.86-2.30) and N (P < .001, 13.59-5.70) but not for P (P = .141, 8.21-3.53). Total Ti release did not differ between groups (P = .36) but was less variable across group P. On average, total ion release was 13.77 ppb (interquartile range 8.91-26.03 ppb) across the 12-month simulation. Tribocorrosion of Ti implants coupled with Au abutments in a simulated environment was evidenced by fretted particles, pitting, and crevice corrosion of the coupling surfaces and release of ions. More Ti was released compared with Pd, Pt, and Au and continued to increase with time. Abutment composition influenced ion release. Au-plated abutments appeared to subdue variation in and minimize high-concentration spikes of titanium.

Mediotrusive Occlusal Contacts: Best Evidence Consensus Statement.

PURPOSE: The impact of mediotrusive (MT) occlusal contacts has been a topic of controversy and confusion in both clinical practice and in the dental literature. The purpose of this Best Evidence Consensus Statement was to explore whether MT interferences are harmful in the natural or therapeutic occlusion directed by 4 focus questions relating to prevalence, jaw function, jaw dysfunction and biomechanical models. MATERIALS AND METHODS: An electronic search in October 2020 sought evidence in MEDLINE (Ovid) using (mediotrus* OR nonworking side OR nonworking contact OR balancing side OR interfer* side OR premature contact) in the multipurpose (.mp) search field; and in Google Scholar using permutations of the above. Supplementary articles were sourced from the associated reference lists. There was no language restriction. The search yield was reviewed in duplicate. RESULTS: The electronic search identified 420 articles. Following screening, 164 were selected for eligibility assessments. Of these, 47 were included in the current paper. CONCLUSIONS: Non-standardized nomenclature and methodology is used to identify MT interferences in patient populations, with resultant prevalence varying from 0% to 77%, (median = 16%). MT interferences may alter the biomechanics of mandibular function. Together with the presence of repeated high loads resultant strain can manifest as pathophysiology of the temporomandibular joint and associated muscle structures. MT interferences should be avoided in any therapeutic occlusal scheme to minimize pulpal, periodontal, structural and mechanical complications or exacerbation of temporomandibular disorders (TMDs). Naturally occurring molar MT interferences should be eliminated only if signs and symptoms of TMDs are present. Literature supports there being a biomechanical basis which can explain how MT interferences may affect temporomandibular joint morphology and jaw function.

An Overview of Machine Learning and Big Data for Drug Toxicity Evaluation.

Drug toxicity evaluation is an essential process of drug development as it is reportedly responsible for the attrition of approximately 30% of drug candidates. The rapid increase in the number and types of large toxicology data sets together with the advances in computational methods may be used to improve many steps in drug safety evaluation. The development of in silico models to screen and understand mechanisms of drug toxicity may be particularly beneficial in the early stages of drug development where early toxicity assessment can most reduce expenses and labor time. To facilitate this, machine learning methods have been employed to evaluate drug toxicity but are often limited by small and less diverse data sets. Recent advances in machine learning methods together with the rapid increase in big toxicity data such as molecular descriptors, toxicogenomics, and high-throughput bioactivity data may help alleviate some of the current challenges. In this article, the most common machine learning methods used in toxicity assessment are reviewed together with examples of toxicity studies that have used machine learning methodology. Furthermore, a comprehensive overview of the different types of toxicity tools and data sets available to build in silico toxicity prediction models has been provided to give an overview of the current big toxicity data landscape and highlight opportunities and challenges related to them.

The efficacy of ultrasonic and PIPS (photon-induced acoustic streaming) irrigation to remove artificially placed dentine debris plugs out of an artificial and natural root model.

The aim was to validate an artificial resin 'root canal wall groove model' (RCWGM) mimicking the situation of natural roots with a groove of identical dimensions on debris removal out of these grooves, and to evaluate Erbium 'laser-activated irrigation' (LAI) with two conical tips at PIPS (photon-induced photoacoustic streaming) settings, with different activation times and different root canal positions on debris removal out of the grooves. A split RCWGM was used (resin blocks and roots of maxillary canines) with a canal size 40/0.06. The grooves in the apical third were filled with stained dentinal debris. Seventeen irrigation protocols (n = 20) were used: syringe-needle irrigation (3× 20 s), manual dynamic activation (1× 60 s), ultrasonically activated irrigation (UAI) with 25/25 Irrisafe (3× 20 s) and LAI (2940 nm Er:YAG) with X-Pulse or PIPS tips at PIPS settings (20 mJ, 50 µs, 20 Hz) and with the fibre (IN) or (OUT) the canal: IN during 1× 20 s, and OUT during 1× 20 s, 2× 20 s, 3× 20 s, 30 s, 2× 30 s and 1× 60 s. The quantity of remaining dentine debris in the groove was evaluated on a numerical scale. Statistical analysis was performed by means of proportional odds logistic regression, equivalence testing and Wald tests. The level of significance was set at 0.05. Resin models and the RCWGM with natural teeth can be called equivalent (log odds ratio 0.185). There were mostly no statistically significant differences for debris removal between UAI and LAI (p > 0.05) and between LAI with PIPS and X-Pulse (p > 0.05). Although not statistically different, the numbers of completely cleaned grooves were higher with LAI than with UAI for a 1-min activation, confirming findings from other studies. There is no difference in cleaning efficacy between X-Pulse and PIPS tips at PIPS settings.