Impact of donor NKG2D and MICA gene polymorphism on clinical outcomes of adult and paediatric allogeneic cord blood transplantation for malignant diseases.

OBJECTIVES: NKG2D is an activating receptor expressed by natural killer (NK) and CD8+ T cells and activation intensity varies by NKG2D expression level or nature of its ligand. An NKG2D gene polymorphism determines high (HNK1) or low (LNK1) expression. MICA is the most polymorphic NKG2D ligand and stronger effector cell activation associates with methionine rather than valine at residue 129. We investigated correlation between cord blood (CB) NKG2D and MICA genotypes and haematopoietic stem cell (HSC) transplant outcome. METHODS: We retrospectively studied 267 CB HSC recipients (178 adult and 87 paediatric) who underwent transplant for malignant disease between 2007 and 2018, analysing CB graft DNA for NKG2D and MICA polymorphisms using Sanger sequencing. Multivariate analysis was used to correlate these results with transplant outcomes. RESULTS: In adult patients, LNK1 homozygous CB significantly improved 60-day neutrophil engraftment (hazard ratio (HR) 0.6; 95% confidence interval (CI) 0.4-0.9; p = .003). In paediatrics, HNK1 homozygous CB improved 60-day engraftment (HR 0.4; 95% CI 0.2-0.7; p = .003), as did MICA-129 methionine+ CB grafts (HR 1.7 95% CI 1.1-2.6; p = .02). CONCLUSION: CB NKG2D and MICA genotypes potentially improve CB HSC engraftment. However, results contrast between adult and paediatric recipients and may reflect transplant procedure disparities between cohorts.

Multidisciplinary approach to severe intracranial, intraorbital allergic fungal sinusitis.

BACKGROUND: Allergic fungal sinusitis (AFS) is a form of paranasal mycosis that often involves bone destruction and can extend into the orbit and anterior skull base. Intracranial and intraorbital involvement are published but not both in each included patient of a series. The purpose of the present study was to review cases of extensive AFS with orbital or/and skull base erosion, including the presenting symptoms, patient socioeconomic background, imaging features, surgical technique, and post-operative outcomes. METHODS: The records of 30 patients with the histological diagnosis of AFS and both intracranial and intraorbital involvement were reviewed. RESULTS: The average age of the patients was 25.2 years. 83 % of patients were male. 70 % were African American. 66 % of patients had Medicaid or were uninsured. Presenting symptoms were headaches (80 %), nasal obstruction (33 %), proptosis (40 %), vision change (23 %), facial pressure (10 %), and decreased sense of smell (7 %). 100 % of patients had bone erosion observed on computerized tomography scans with disease extending intracranially through the anterior skull base or posterior wall of the frontal sinus along with disease that eroded through the lamina papyracea. All patients had failed medical management. All patients underwent surgery by Otolaryngology, Ophthalmology, and Neurosurgery with transnasal endoscopic approaches and orbitotomy. 80 % also underwent a bifrontal craniotomy for removal of intracranial extradural disease with cranialization. 53 % of patients had orbital implants remaining after surgery; 23 % had nasal stents. There were no postoperative cerebrospinal fluid leaks. Average hospital stay was 4.8 days. Preoperatively, 13 % of patients underwent allergy testing. 94 % saw an Allergist postoperatively. 21 % required follow up surgery. CONCLUSIONS: A team approach of Otolaryngologists, Ophthalmologists, and Neurosurgeons is recommended for this slowly growing but locally destructive disease. Most patients with AFS will present with headaches and nasal obstruction. While most cases of AFS can be successfully managed with transnasal endoscopic techniques, orbitotomy and craniotomy represents an effective treatment for severe AFS cases with extensive intracranial and intraorbital involvement. This disease is found most commonly in young African American males and in the underinsured.

An acoustic study of Cantonese alaryngeal speech in different speaking conditions.

Esophageal (ES) speech, tracheoesophageal (TE) speech, and the electrolarynx (EL) are common methods of communication following the removal of the larynx. Our recent study demonstrated that intelligibility may increase for Cantonese alaryngeal speakers using clear speech (CS) compared to their everyday "habitual speech" (HS), but the reasoning is still unclear [Hui, Cox, Huang, Chen, and Ng (2022). Folia Phoniatr. Logop. 74, 103-111]. The purpose of this study was to assess the acoustic characteristics of vowels and tones produced by Cantonese alaryngeal speakers using HS and CS. Thirty-one alaryngeal speakers (9 EL, 10 ES, and 12 TE speakers) read The North Wind and the Sun passage in HS and CS. Vowel formants, vowel space area (VSA), speaking rate, pitch, and intensity were examined, and their relationship to intelligibility were evaluated. Statistical models suggest that larger VSAs significantly improved intelligibility, but slower speaking rate did not. Vowel and tonal contrasts did not differ between HS and CS for all three groups, but the amount of information encoded in fundamental frequency and intensity differences between high and low tones positively correlated with intelligibility for TE and ES groups, respectively. Continued research is needed to understand the effects of different speaking conditions toward improving acoustic and perceptual characteristics of Cantonese alaryngeal speech.

The Effect of Clear Speech on Cantonese Alaryngeal Speakers' Intelligibility.

BACKGROUND/AIM: The purpose of this study was to provide preliminary data concerning the effect of clear speech (CS) on Cantonese alaryngeal speakers' intelligibility. METHODS: Voice recordings of 11 sentences randomly selected from the Cantonese Sentence Intelligibility Test (CSIT) were obtained from 31 alaryngeal speakers (9 electrolarynx [EL] users, 10 esophageal speakers and 12 tracheoesophageal [TE] speakers) in habitual speech (HS) and CS. Two naïve listeners orthographically transcribed a total of 1,364 sentences. RESULTS: Significant effects of speaking condition on speaking rate and CSIT scores were observed, but no significant effect of alaryngeal communication methods was noted. CS was significantly slower than HS by 0.78 syllables/s. Esophageal speakers demonstrated the slowest speech rate when using CS, while EL users demonstrated the largest decrease in speaking rate when using CS compared to HS. TE speakers had the highest CSIT scores in HS (listener 1 = 81.4%; listener 2 = 81.3%), and esophageal speakers had the highest CSIT scores in CS (listener 1 = 87.5%; listener 2 = 89.7%). EL users experienced the largest increase in intelligibility while using CS compared to HS (9.1%) followed by esophageal speakers (8.9%) and TE speakers (1.4%). CONCLUSION: Preliminary data indicate that CS may significantly affect Cantonese alaryngeal speakers' speaking rate and intelligibility. However, intelligibility appeared to vary considerably across speakers. Further research involving larger, heterogeneous groups of speakers and listeners alongside longer and more refined CS training protocols should be conducted to confirm that CS can improve Cantonese alaryngeal speakers' intelligibility.

Major Histocompatibility Complex Class I Chain-Related A and B (MICA and MICB) Gene, Allele, and Haplotype Associations With Dengue Infections in Ethnic Thais.

BACKGROUND: Major histocompatibility complex class I chain-related (MIC) A and B (MICA and MICB) are polymorphic stress molecules recognized by natural killer cells. This study was performed to analyze MIC gene profiles in hospitalized Thai children with acute dengue illness. METHODS: MIC allele profiles were determined in a discovery cohort of patients with dengue fever or dengue hemorrhagic fever (DHF) (n = 166) and controls (n = 149). A replication cohort of patients with dengue (n = 222) was used to confirm specific MICB associations with disease. RESULTS: MICA*045 and MICB*004 associated with susceptibility to DHF in secondary dengue virus (DENV) infections (odds ratio [OR], 3.22; [95% confidence interval (CI), 1.18-8.84] and 1.99 [1.07-2.13], respectively), and MICB*002 with protection from DHF in secondary DENV infections (OR, 0.41; 95% CI, .21-.68). The protective effect of MICB*002 against secondary DHF was confirmed in the replication cohort (OR, 0.43; 95% CI, .22-.82) and was stronger when MICB*002 is present in individuals also carrying HLA-B*18, B*40, and B*44 alleles which form the B44 supertype of functionally related alleles (0.29, 95% CI, .14-.60). CONCLUSIONS: Given that MICB*002 is a low expresser of soluble proteins, these data indicate that surface expression of MICB*002 with B44 supertype alleles on DENV-infected cells confer a protective advantage in controlling DENV infection using natural killer cells.

ROBOKOP: an abstraction layer and user interface for knowledge graphs to support question answering.

SUMMARY: Knowledge graphs (KGs) are quickly becoming a common-place tool for storing relationships between entities from which higher-level reasoning can be conducted. KGs are typically stored in a graph-database format, and graph-database queries can be used to answer questions of interest that have been posed by users such as biomedical researchers. For simple queries, the inclusion of direct connections in the KG and the storage and analysis of query results are straightforward; however, for complex queries, these capabilities become exponentially more challenging with each increase in complexity of the query. For instance, one relatively complex query can yield a KG with hundreds of thousands of query results. Thus, the ability to efficiently query, store, rank and explore sub-graphs of a complex KG represents a major challenge to any effort designed to exploit the use of KGs for applications in biomedical research and other domains. We present Reasoning Over Biomedical Objects linked in Knowledge Oriented Pathways as an abstraction layer and user interface to more easily query KGs and store, rank and explore query results. AVAILABILITY AND IMPLEMENTATION: An instance of the ROBOKOP UI for exploration of the ROBOKOP Knowledge Graph can be found at http://robokop.renci.org. The ROBOKOP Knowledge Graph can be accessed at http://robokopkg.renci.org. Code and instructions for building and deploying ROBOKOP are available under the MIT open software license from https://github.com/NCATS-Gamma/robokop. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

A semantic similarity based methodology for predicting protein-protein interactions: Evaluation with P53-interacting kinases.

Biomedical literature contains unstructured, rich information regarding proteins, ligands, diseases as well as biological pathways in which they are involved. Systematically analyzing such textual corpus has the potential for biomedical discovery of new protein-protein interactions and hidden drug indications. For this purpose, we have investigated a methodology that is based on a well-established text mining tool, Word2Vec, for the analysis of PubMed full text articles to derive word embeddings, and the use of a simple semantic similarity comparison either by itself or in conjunction with k-Nearest Neighbor (kNN) technique for the prediction of new relationships. To test this methodology, three lines of retrospective analyses of a dataset with known P53-interacting proteins have been conducted. First, we demonstrated that Word2Vec semantic similarity can infer functional relatedness among all kinases known to interact with P53. Second, in a series of time-split experiments, we demonstrated that both a simple similarity comparison and kNN models built with papers published up to a certain year were able to discover P53 interactors described in later publications. Third, in a different scenario of time-split experiments, we examined the predictions of P53-interacting proteins based on the kNN models built on data prior to a certain split year for different time ranges past that year, and found that the cumulative number of correct predictions was indeed increasing with time. We conclude that text mining of research papers in the PubMed literature based on Word2Vec analysis followed by a simple similarity comparison or kNN modeling affords excellent predictions of protein-protein interactions between P53 and kinases, and should have wide applications in translational biomedical studies such as repurposing of existing drugs, drug-drug interaction, and elucidation of mechanisms of action for drugs.

FHIR PIT: an open software application for spatiotemporal integration of clinical data and environmental exposures data.

BACKGROUND: Informatics tools to support the integration and subsequent interrogation of spatiotemporal data such as clinical data and environmental exposures data are lacking. Such tools are needed to support research in environmental health and any biomedical field that is challenged by the need for integrated spatiotemporal data to examine individual-level determinants of health and disease. RESULTS: We have developed an open-source software application-FHIR PIT (Health Level 7 Fast Healthcare Interoperability Resources Patient data Integration Tool)-to enable studies on the impact of individual-level environmental exposures on health and disease. FHIR PIT was motivated by the need to integrate patient data derived from our institution's clinical warehouse with a variety of public data sources on environmental exposures and then openly expose the data via ICEES (Integrated Clinical and Environmental Exposures Service). FHIR PIT consists of transformation steps or building blocks that can be chained together to form a transformation and integration workflow. Several transformation steps are generic and thus can be reused. As such, new types of data can be incorporated into the modular FHIR PIT pipeline by simply reusing generic steps or adding new ones. We validated FHIR PIT in the context of a driving use case designed to investigate the impact of airborne pollutant exposures on asthma. Specifically, we replicated published findings demonstrating racial disparities in the impact of airborne pollutants on asthma exacerbations. CONCLUSIONS: While FHIR PIT was developed to support our driving use case on asthma, the software can be used to integrate any type and number of spatiotemporal data sources at a level of granularity that enables individual-level study. We expect FHIR PIT to facilitate research in environmental health and numerous other biomedical disciplines.

Production of Vowels by Electrolaryngeal Speakers Using Clear Speech.

BACKGROUND/AIMS: This study examined the effect of clear speech on vowel productions by electrolaryngeal speakers. METHOD: Ten electrolaryngeal speakers produced eighteen words containing /i/, /ɪ/, /ɛ/, /æ/, /eɪ/, and /oʊ/ using habitual speech and clear speech. Twelve listeners transcribed 360 words, and a total of 4,320 vowel stimuli across speaking conditions, speakers, and listeners were analyzed. Analyses included listeners' identifications of vowels, vowel duration, and vowel formant relationships. RESULTS: No significant effect of speaking condition was found on vowel identification. Specifically, 85.4% of the vowels were identified in habitual speech, and 82.7% of the vowels were identified in clear speech. However, clear speech was found to have a significant effect on vowel durations. The mean vowel duration in the 17 consonant-vowel-consonant words was 333 ms in habitual speech and 354 ms in clear speech. The mean vowel duration in the single consonant-vowel words was 551 ms in habitual speech and 629 ms in clear speech. CONCLUSION: Finding suggests that, although clear speech facilitates longer vowel durations, electrolaryngeal speakers may not gain a clear speech benefit relative to listeners' vowel identifications.

ROBOKOP KG and KGB: Integrated Knowledge Graphs from Federated Sources.

A proliferation of data sources has led to the notional existence of an implicit Knowledge Graph (KG) that contains vast amounts of biological knowledge contributed by distributed Application Programming Interfaces (APIs). However, challenges arise when integrating data across multiple APIs due to incompatible semantic types, identifier schemes, and data formats. We present ROBOKOP KG ( http://robokopkg.renci.org ), which is a KG that was initially built to support the open biomedical question-answering application, ROBOKOP (Reasoning Over Biomedical Objects linked in Knowledge-Oriented Pathways) ( http://robokop.renci.org ). Additionally, we present the ROBOKOP Knowledge Graph Builder (KGB), which constructs the KG and provides an extensible framework to handle graph query over and integration of federated data sources.

Modulation of Orthographic Decoding by Frontal Cortex.

Opinions are divided on whether word reading processes occur in a hierarchical, feedforward fashion or within an interactive framework. To critically evaluate these competing theories, we recorded electrocorticographic (ECoG) data from 15 human patients with intractable epilepsy during a word completion task and evaluated brain network dynamics across individuals. We used a novel technique of analyzing multihuman ECoG recordings to identify cortical regions most relevant to processing lexical information. The mid fusiform gyrus showed the strongest, earliest response after stimulus onset, whereas activity was maximal in frontal, dorsal lateral prefrontal, and sensorimotor regions toward articulation onset. To evaluate interregional functional connectivity, ECoG data from electrodes situated over specific cortical regions of interest were fit into linear multivariate autoregressive (MVAR) models. Spectral characteristics of the MVAR models were used to precisely reveal the timing and the magnitude of information flow between localized brain regions. This is the first application of MVAR for developing a comprehensive account of interregional interactions from a word reading ECoG dataset. Our comprehensive findings revealed both top-down and bottom-up influences between higher-level language areas and the mid fusiform gyrus. Our findings thus challenge strictly hierarchical, feedforward views of word reading and suggest that orthographic processes are modulated by prefrontal and sensorimotor regions via an interactive framework. SIGNIFICANCE STATEMENT: Word reading is a critical part of everyday life. When the ability to read is disrupted, it can lead to learning disorders, as well as emotional and academic difficulties. The neural mechanisms underlying word reading are not well understood due to limitations in the spatial and temporal specificity of prior word reading studies. Our research analyzed data recorded from sensors implanted directly from surface of human brains while these individuals performed a word reading task. Our research analyzed these recordings to infer how brain regions communicate during word reading. Our original results improve upon current models of word reading and can be used to develop treatment plans for individuals with reading disabilities.

Transformation of Cerium Oxide Nanoparticles from a Diesel Fuel Additive during Combustion in a Diesel Engine.

Nanoscale cerium oxide is used as a diesel fuel additive to reduce particulate matter emissions and increase fuel economy, but its fate in the environment has not been established. Cerium oxide released as a result of the combustion of diesel fuel containing the additive Envirox, which utilizes suspended nanoscale cerium oxide to reduce particulate matter emissions and increase fuel economy, was captured from the exhaust stream of a diesel engine and was characterized using a combination of bulk analytical techniques and high resolution transmission electron microscopy. The combustion process induced significant changes in the size and morphology of the particles; ∼15 nm aggregates consisting of 5-7 nm faceted crystals in the fuel additive became 50-300 nm, near-spherical, single crystals in the exhaust. Electron diffraction identified the original cerium oxide particles as cerium(IV) oxide (CeO2, standard FCC structure) with no detectable quantities of Ce(III), whereas in the exhaust the ceria particles had additional electron diffraction reflections indicative of a CeO2 superstructure containing ordered oxygen vacancies. The surfactant coating present on the cerium oxide particles in the additive was lost during combustion, but in roughly 30% of the observed particles in the exhaust, a new surface coating formed, approximately 2-5 nm thick. The results of this study suggest that pristine, laboratory-produced, nanoscale cerium oxide is not a good substitute for the cerium oxide released from fuel-borne catalyst applications and that future toxicity experiments and modeling will require the use/consideration of more realistic materials.

Adsorption of Phthalates on Impervious Indoor Surfaces.

Sorption of semivolatile organic compounds (SVOCs) onto interior surfaces, often referred to as the "sink effect", and their subsequent re-emission significantly affect the fate and transport of indoor SVOCs and the resulting human exposure. Unfortunately, experimental challenges and the large number of SVOC/surface combinations have impeded progress in understanding sorption of SVOCs on indoor surfaces. An experimental approach based on a diffusion model was thus developed to determine the surface/air partition coefficient K of di-2-ethylhexyl phthalate (DEHP) on typical impervious surfaces including aluminum, steel, glass, and acrylic. The results indicate that surface roughness plays an important role in the adsorption process. Although larger data sets are needed, the ability to predict K could be greatly improved by establishing the nature of the relationship between surface roughness and K for clean indoor surfaces. Furthermore, different surfaces exhibit nearly identical K values after being exposed to kitchen grime with values that are close to those reported for the octanol/air partition coefficient. This strongly supports the idea that interactions between gas-phase DEHP and soiled surfaces have been reduced to interactions with an organic film. Collectively, the results provide an improved understanding of equilibrium partitioning of SVOCs on impervious surfaces.

Examining transgender health through the International Classification of Functioning, Disability, and Health's (ICF) Contextual Factors.

PURPOSE: For many transgender individuals, medical intervention is necessary to live as their desired gender. However, little is known about Contextual Factors (i.e., Environmental and Personal) that may act as facilitators and barriers in the health of transgender individuals. Therefore, this paper sought to examine Contextual Factors of the World Health Organization's International Classification of Functioning, Disability, and Health that may facilitate or negatively impact the physical, psychological, and social functioning of transgender individuals. METHODS: A literature review was conducted to identify Environmental and Personal Factors that may influence transgender individuals' physical, psychological, and social functioning. Seven electronic databases were searched. In total, 154 records were reviewed, and 41 articles and other records met inclusion criteria. RESULTS: Three general themes emerged for Environmental Factors: family and social networks, education, and health care. Three general themes also emerged for Personal Factors: socioeconomic status, race, and age. CONCLUSIONS: Transgender individuals benefit from gender-affirming services, improved family and social support systems, and competent provider care. Educational training programs, including medical curricula or workshops, might provide the greatest benefit in improving transgender health by increasing the knowledge and cultural competency of health professionals working with this population. Given the diversity of gender expression, differences in lived experiences, and potential for enduring persistent "double discrimination" due to the intersectional relationships between socioeconomic status, race, and/or age, health professionals must approach transgender health using a holistic lens such as the World Health Organization's International Classification of Functioning, Disability, and Health.

The morbidity and mortality of hepaticojejunostomies for complex bile duct injuries: a multi-institutional analysis of risk factors and outcomes using NSQIP.

INTRODUCTION: Bile duct injury (BDI) is an infrequent but morbid complication of cholecystectomy. High-grade BDI repairs requiring hepaticojejunostomies are complex and associated with increased morbidity and mortality. This study sought to establish the increased risk associated with complex bile duct repair at a multi-institutional level in the United States. METHODS: Using the ACS-NSQIP Participant Use File, all patients who underwent a hepaticojejunostomy for bile duct repair between 2005 and 2012 were identified. Clinical data, perioperative risk factors and morbidity and mortality rates were calculated. RESULTS: Of the 293 BDI patients, 102 (65.2%) were female and the mean age was 49.8 years. The 30-day morbidity and mortality rates were 26.3% and 2%, respectively. Univariable analysis identified male gender, ASA class, functional status, diabetes, hypertension and chronic steroid use to be associated with increased morbidity. A higher ASA class was associated with increased postoperative sepsis and chronic steroid use was associated with increased overall morbidity on multivariable analysis. The morbidity rates for BDI repair within 30 days of injury vs. later repair were similar (24% vs. 23%), but the mortality rate was higher for the earlier repair group (5% vs. 0%, p = 0.012). CONCLUSIONS: Within the largest multi-institutional analysis of 30-day outcomes after hepaticojejunostomies for BDI in the US, morbidity and mortality rates were established at 26.3% and 2% respectively. ASA class and preoperative functional status remain the main risk factors for surgery. Earlier repair in the face of ongoing sepsis and disability is associated with worse outcomes. A multidisciplinary approach at a specialized center aimed at controlling infection and improving functional status prior to surgical reconstruction is recommended.

Umbilical cord blood plasma contains soluble NKG2D ligands that mediate loss of natural killer cell function and cytotoxicity.

NK cells play a key role in innate elimination of virally infected or neoplastic cells but they can be circumvented by immunoevasive mechanisms enabling viral spread or tumor progression. Engagement of the NKG2D activating receptor with soluble forms of its ligand is one such mechanism of inducing NK cell hyporesponsiveness. Interestingly, this immunoevasive strategy among others is described at the maternal-fetal interface where tolerance of the semi-allogeneic fetus is required to allow successful human pregnancy. Understanding of maternal-fetal tolerance is increasing but mechanisms preventing alloreactivity of fetal immune cells against the maternal host are less well understood. The study of umbilical cord blood has enabled insight of the fetal immune system, which appears immature and inert. We have found that soluble NKG2D ligands (sNKG2DLs) are present in cord blood plasma (CBP) and associate with adult NK cell hyporesponsiveness demonstrated by reduced CD107a expression and secretion of IFN-γ upon stimulation. The capacity of NK cells to kill K562 cells or proliferate was also reduced by incubation with CBP; however, physical removal of sNKG2DL from CBP restored K562 lytic function and NKG2D expression. Therefore, our results strongly suggest sNKG2DLs are expressed in CBP as a mechanism of fetal-maternal tolerance in human pregnancy.

Diffusion-controlled toluene reference material for VOC emissions testing: international interlaboratory study.

UNLABELLED: The measurement of volatile organic compound (VOC) emissions from building products and materials by manufacturers and testing laboratories, and the use of the test results for labeling programs, continue to expand. One issue that hinders wide acceptance for chamber product testing is the lack of a reference material to validate test chamber performance. To meet this need, the National Institute of Standards and Technology (NIST) and Virginia Tech (VT) have developed a prototype reference material that emits a single VOC similar to the emissions of a diffusion-controlled building product source with a dynamic emissions profile. The prototype material has undergone extensive testing at NIST and a pilot interlaboratory study (ILS) with four laboratories. The next development step is an evaluation of the prototype source in multiple-sized chambers of 14 laboratories in seven countries. Each laboratory was provided duplicate specimens and a test protocol. Study results identified significant issues related to the need to store the source at a subzero Celsius temperature until tested and possible inconsistencies in large chambers. For laboratories using a small chamber and meeting all the test method criteria, the results were very encouraging with relative standard deviations ranging from 5% to 10% across the laboratories. IMPLICATIONS: Currently, the chamber performance of laboratories conducting product VOC emissions testing is assessed through interlaboratory studies (ILS) using a source with an unknown emission rate. As a result, laboratory proficiency can only be based on the mean and standard deviation of emission rates measured by the participating ILS laboratories. A reference material with a known emission rate has the potential to provide an independent assessment of laboratory performance as well as improve the quality of interlaboratory studies. Several international laboratories with different chamber testing systems demonstrated the ability to measure the emission rate of such a reference material within an acceptable measurement uncertainty.

Characterisation of RAET1E/ULBP4 exon 4 and 3' untranslated region genetic architecture reveals further diversity and allelic polymorphism.

NKG2D is a natural killer cell activating receptor recognising ligands on infected or tumorigenic cells, leading to their cytolysis. There are eight known genes encoding NKG2D ligands: MICA, MICB and ULBP1-6. MICA and MICB are highly polymorphic and well characterised, whilst ULBP ligands are less polymorphic and the functional implication of their diversity is not well understood. Using International HLA and Immunogenetics Workshop (IHIW) cell line DNA, we previously characterised alleles of the RAET1E gene (encoding ULBP4 proteins), including the 5' UTR promoter region and exons 1-3. We found 11 promoter haplotypes associating with alleles based on exons 1-3, revealing 19 alleles overall. The current study extends this analysis using 87 individual DNA samples from IHIW cell lines or cord blood to include RAET1E exon 4 and the 3' UTR, as polymorphism in these regions have not been previously investigated. We found two novel exon 4 polymorphisms encoding amino acid substitutions altering the transmembrane domain. An amino acid substitution at residue 233 was unique to the RAET1E*008 allele whereas the substitution at residue 237 was shared between groups of alleles. Additionally, four haplotypes were found based on 3' UTR sequences, which were unique to certain alleles or shared with allele groups based on exons 1-4 polymorphisms. Furthermore, putative microRNAs were identified that may interact with these polymorphic sites, repressing transcription and potentially affecting expression levels.

Structure-preserving model reduction of passive and quasi-active neurons.

The spatial component of input signals often carries information crucial to a neuron's function, but models mapping synaptic inputs to the transmembrane potential can be computationally expensive. Existing reduced models of the neuron either merge compartments, thereby sacrificing the spatial specificity of inputs, or apply model reduction techniques that sacrifice the underlying electrophysiology of the model. We use Krylov subspace projection methods to construct reduced models of passive and quasi-active neurons that preserve both the spatial specificity of inputs and the electrophysiological interpretation as an RC and RLC circuit, respectively. Each reduced model accurately computes the potential at the spike initiation zone (SIZ) given a much smaller dimension and simulation time, as we show numerically and theoretically. The structure is preserved through the similarity in the circuit representations, for which we provide circuit diagrams and mathematical expressions for the circuit elements. Furthermore, the transformation from the full to the reduced system is straightforward and depends on intrinsic properties of the dendrite. As each reduced model is accurate and has a clear electrophysiological interpretation, the reduced models can be used not only to simulate morphologically accurate neurons but also to examine computations performed in dendrites.