Development of an adverse outcome pathway network for nephrotoxicity.

Adverse outcome pathways (AOPs) were introduced in modern toxicology to provide evidence-based representations of the events and processes involved in the progression of toxicological effects across varying levels of the biological organisation to better facilitate the safety assessment of chemicals. AOPs offer an opportunity to address knowledge gaps and help to identify novel therapeutic targets. They also aid in the selection and development of existing and new in vitro and in silico test methods for hazard identification and risk assessment of chemical compounds. However, many toxicological processes are too intricate to be captured in a single, linear AOP. As a result, AOP networks have been developed to aid in the comprehension and placement of associated events underlying the emergence of related forms of toxicity-where complex exposure scenarios and interactions may influence the ultimate adverse outcome. This study utilised established criteria to develop an AOP network that connects thirteen individual AOPs associated with nephrotoxicity (as sourced from the AOP-Wiki) to identify several key events (KEs) linked to various adverse outcomes, including kidney failure and chronic kidney disease. Analysis of the modelled AOP network and its topological features determined mitochondrial dysfunction, oxidative stress, and tubular necrosis to be the most connected and central KEs. These KEs can provide a logical foundation for guiding the selection and creation of in vitro assays and in silico tools to substitute for animal-based in vivo experiments in the prediction and assessment of chemical-induced nephrotoxicity in human health.

Societal importance of Antarctic negative feedbacks on climate change: blue carbon gains from sea ice, ice shelf and glacier losses.

Diminishing prospects for environmental preservation under climate change are intensifying efforts to boost capture, storage and sequestration (long-term burial) of carbon. However, as Earth's biological carbon sinks also shrink, remediation has become a key part of the narrative for terrestrial ecosystems. In contrast, blue carbon on polar continental shelves have stronger pathways to sequestration and have increased with climate-forced marine ice losses-becoming the largest known natural negative feedback on climate change. Here we explore the size and complex dynamics of blue carbon gains with spatiotemporal changes in sea ice (60-100 MtCyear-1), ice shelves (4-40 MtCyear-1 = giant iceberg generation) and glacier retreat (< 1 MtCyear-1). Estimates suggest that, amongst these, reduced duration of seasonal sea ice is most important. Decreasing sea ice extent drives longer (not necessarily larger biomass) smaller cell-sized phytoplankton blooms, increasing growth of many primary consumers and benthic carbon storage-where sequestration chances are maximal. However, sea ice losses also create positive feedbacks in shallow waters through increased iceberg movement and scouring of benthos. Unlike loss of sea ice, which enhances existing sinks, ice shelf losses generate brand new carbon sinks both where giant icebergs were, and in their wake. These also generate small positive feedbacks from scouring, minimised by repeat scouring at biodiversity hotspots. Blue carbon change from glacier retreat has been least well quantified, and although emerging fjords are small areas, they have high storage-sequestration conversion efficiencies, whilst blue carbon in polar waters faces many diverse and complex stressors. The identity of these are known (e.g. fishing, warming, ocean acidification, non-indigenous species and plastic pollution) but not their magnitude of impact. In order to mediate multiple stressors, research should focus on wider verification of blue carbon gains, projecting future change, and the broader environmental and economic benefits to safeguard blue carbon ecosystems through law.

Variation in zoobenthic blue carbon in the Arctic's Barents Sea shelf sediments.

The flow of carbon from atmosphere to sediment fauna and sediments reduces atmospheric CO2, which in turn reduces warming. Here, during the Changing Arctic Ocean Seafloor programme, we use comparable methods to those used in the Antarctic (vertical, calibrated camera drops and trawl-collected specimens) to calculate the standing stock of zoobenthic carbon throughout the Barents Sea. The highest numbers of morphotypes, functional groups and individuals were found in the northernmost sites (80-81.3° N, 29-30° E). Ordination (non-metric multidimensional scaling) suggested a cline of faunal transition from south to north. The functional group dominance differed across all six sites, despite all being apparently similar muds. Of the environmental variables we measured, only water current speed could significantly explain any of our spatial carbon differences. We found no obvious relationship with sea ice loss and thus no evidence of Arctic blue carbon-climate feedback. Blue carbon in the Barents Sea can be comparable with the highest levels in Antarctic shelf sediments. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.

Whole-genome sequencing reveals clinically relevant insights into the aetiology of familial breast cancers.

BACKGROUND: Whole-genome sequencing (WGS) is a powerful method for revealing the diversity and complexity of the somatic mutation burden of tumours. Here, we investigated the utility of tumour and matched germline WGS for understanding aetiology and treatment opportunities for high-risk individuals with familial breast cancer. PATIENTS AND METHODS: We carried out WGS on 78 paired germline and tumour DNA samples from individuals carrying pathogenic variants in BRCA1 (n = 26) or BRCA2 (n = 22) or from non-carriers (non-BRCA1/2; n = 30). RESULTS: Matched germline/tumour WGS and somatic mutational signature analysis revealed patients with unreported, dual pathogenic germline variants in cancer risk genes (BRCA1/BRCA2; BRCA1/MUTYH). The strategy identified that 100% of tumours from BRCA1 carriers and 91% of tumours from BRCA2 carriers exhibited biallelic inactivation of the respective gene, together with somatic mutational signatures suggestive of a functional deficiency in homologous recombination. A set of non-BRCA1/2 tumours also had somatic signatures indicative of BRCA-deficiency, including tumours with BRCA1 promoter methylation, and tumours from carriers of a PALB2 pathogenic germline variant and a BRCA2 variant of uncertain significance. A subset of 13 non-BRCA1/2 tumours from early onset cases were BRCA-proficient, yet displayed complex clustered structural rearrangements associated with the amplification of oncogenes and pathogenic germline variants in TP53, ATM and CHEK2. CONCLUSIONS: Our study highlights the role that WGS of matched germline/tumour DNA and the somatic mutational signatures can play in the discovery of pathogenic germline variants and for providing supporting evidence for variant pathogenicity. WGS-derived signatures were more robust than germline status and other genomic predictors of homologous recombination deficiency, thus impacting the selection of platinum-based or PARP inhibitor therapy. In this first examination of non-BRCA1/2 tumours by WGS, we illustrate the considerable heterogeneity of these tumour genomes and highlight that complex genomic rearrangements may drive tumourigenesis in a subset of cases.

Modeling observations of solar coronal mass ejections with heliospheric imagers verified with the Heliophysics System Observatory.

We present an advance toward accurately predicting the arrivals of coronal mass ejections (CMEs) at the terrestrial planets, including Earth. For the first time, we are able to assess a CME prediction model using data over two thirds of a solar cycle of observations with the Heliophysics System Observatory. We validate modeling results of 1337 CMEs observed with the Solar Terrestrial Relations Observatory (STEREO) heliospheric imagers (HI) (science data) from 8 years of observations by five in situ observing spacecraft. We use the self-similar expansion model for CME fronts assuming 60° longitudinal width, constant speed, and constant propagation direction. With these assumptions we find that 23%-35% of all CMEs that were predicted to hit a certain spacecraft lead to clear in situ signatures, so that for one correct prediction, two to three false alarms would have been issued. In addition, we find that the prediction accuracy does not degrade with the HI longitudinal separation from Earth. Predicted arrival times are on average within 2.6 ± 16.6 h difference of the in situ arrival time, similar to analytical and numerical modeling, and a true skill statistic of 0.21. We also discuss various factors that may improve the accuracy of space weather forecasting using wide-angle heliospheric imager observations. These results form a first-order approximated baseline of the prediction accuracy that is possible with HI and other methods used for data by an operational space weather mission at the Sun-Earth L5 point.

Investigation of unprovoked venous thromboembolism: a case for a tempered approach?

AIM: To investigate and review the diagnostic yield for occult malignancy in patients who underwent abdominopelvic computed tomography (CT) after the diagnosis of unprovoked venous thromboembolism (VTE) with reference to the guidelines set by The National Institute for Health and Clinical Excellence (NICE). MATERIALS AND METHODS: We retrospectively reviewed all unprovoked VTE diagnosed within a large teaching hospital over a period of 21 months for subsequent imaging investigations and cancer diagnoses. The primary outcome was confirmed cancer diagnosis; patients were followed for a minimum of 12 months. RESULTS: Three hundred and five unprovoked VTEs were diagnosed in the study period, 31% of all VTEs. Of this cohort, 73.1% underwent further imaging for exclusion of occult malignancy. Fifteen (4.9%) cancers were diagnosed; with no subsequent malignancy reported in a 12-month follow-up period of the remaining 290 patients. Of the 15 cancers, seven were post-pulmonary emboli, all of which were identified on the initial CT pulmonary angiogram, thus abdominopelvic CT only was used to locate the primary and to undertake staging. Eight were post-deep-vein thrombosis (DVT). Thus the diagnostic yield for malignancy on abdominopelvic CT post-unprovoked VTE was 2.3%. The majority of diagnosed cancers were advanced with 80% dying in the follow-up period with a mean survival of 3.4 months. CONCLUSION: The pick-up rate of occult malignancy on abdominopelvic CT post-unprovoked VTE in the present study was 2.3%, far less than the generally quoted rate of 10%; however, similar to other rates in the literature. The benefit abdominopelvic CT brings to the diagnosis of occult malignancy post-unprovoked VTE is irresolute.

Blood oxygen equilibration time after cessation of supplemental oxygen in chronic respiratory disease.

BACKGROUND: Measurement of the arterial partial pressure of oxygen (PaO2 ) while breathing air is an informative investigation in patients with hypoxaemia due to chronic respiratory disease, but there are a lack of published data on the time needed for blood oxygen levels to equilibrate after cessation of supplemental oxygen (O2 ) in such patients. AIM: To determine the blood oxygen equilibration time after cessation of O2 and thereby provide guidance on best timing of baseline arterial blood gas analysis in this population. METHODS: Medically stable subjects with chronic respiratory disease were administered O2 at a constant concentration. Continuous pulse oximetry was recorded from before cessation of O2 to beyond the point of oxygen saturation (SpO2 ) equilibration. Data were fitted to an exponential decay model. Blood oxygen equilibration time was defined as the t90, the time taken for SpO2 to fall 90% of the difference between initial (on O2 ) and final (on air) values. RESULTS: Eighty-two (82) subjects with a mean age of 66 years were included. The largest diagnostic category was chronic obstructive pulmonary disease (37), followed by interstitial lung disease (15) and bronchiectasis (12). The median t90 was 6 min 18 s (interquartile range: 4 min 32 s-10 min 30 s). The 95th centile t90 value was 20 min. CONCLUSION: In the majority of patients with chronic respiratory disease, a time delay of 20 min between cessation of supplemental O2 and PaO2 measurement allows confidence that the result is a true baseline value.

Peginterferon and ribavirin for treatment of recurrent hepatitis C disease in HCV-HIV coinfected liver transplant recipients.

Achievement of a sustained virologic response (SVR) with antiviral therapy significantly improves graft survival in hepatitis C virus (HCV) monoinfected liver transplant (LT) patients. Risks and benefits of HCV therapy in HCV-human immunodeficiency virus (HIV) coinfected LT recipients are not well established. Among 89 HCV-HIV LT recipients in the HIVTR cohort, 39 (23% Black, 79% genotype 1, 83% fibrosis stage ≤ 1) were treated with peginterferon-a2a or a2b plus ribavirin for a median 363 days (14-1373). On intent-to-treat basis, 22% (95% CI: 10-39) and 14% (95% CI: 5-30) achieved an end-of-treatment response (EOTR) and SVR, respectively. By per-protocol analysis (completed 48 weeks of therapy ± dose reductions), 42% and 26% had EOTR and SVR, respectively. Severe adverse events occurred in 85%, with 26% hospitalized with infections and 13% developing acute rejection. Early discontinuations and dose reductions occurred in 38% and 82%, respectively, despite use of growth factors in 85%. Eighteen of 39 treated patients (46%) subsequently died/had graft loss, with 10 (26%) attributed to recurrent HCV. In conclusion, SVR rates are low and tolerability is poor in HCV-HIV coinfected transplant recipients treated with peginterferon and ribavirin. These results highlight the critical need for better tolerated and more efficacious HCV therapies for HCV-HIV coinfected transplant recipients.

Hip Fractures: The St Ann's Bay Regional Hospital Experience.

OBJECTIVES: To study the outcome of hip fractures in a cohort of patients from two different time periods (2002-2003 and 2006-2008). METHODS: Patients treated for hip fractures at the St Ann's Bay Regional Hospital (SABRH), which provides orthopaedic care for the parishes of St Ann, St Mary and Portland, were retrospectively analysed between 2002-2003 and 2006-2008. RESULTS: A significant increase in the recorded incidence of hip fractures, from 19 in the 2002-2003 time period to 101 in the 2006-2008 time period was noted. There was a drastic fall in the in-hospital mortality rate (43% in the 2002-2003 time period compared to 4.5% in the 2006-2008 time period). In the 2006-2008 period, 82.9% of patients were ambulant at discharge compared to 36% from the 2002-2003 time period. CONCLUSION: Early surgical fixation is necessary to allow rapid mobilization in these patients for whom the consequences of bed rest would otherwise be devastating.

A comparison of patient-reported outcomes in patients undergoing abdominal wall repair with either synthetic or biosynthetic mesh: a pilot study.

PURPOSE: Repair of midline ventral incisional hernias (VIHR) requires mesh reinforcement. Mesh types can be categorised into synthetic, biosynthetic, or biological. There is a lack of evidence to support one type of mesh over another. The aim of this pilot study was to compare mesh sensation in patients having undergone elective open repair with synthetic or biosynthetic mesh. METHODS: Four years of prospectively collected data were retrospectively reviewed on 40 patients who had undergone VIHR, using either biosynthetic or synthetic mesh placed in the retromuscular plane. The decision on type of mesh used was governed by patient characteristics. Patients were invited to complete the Carolinas Comfort Scale (CCS) questionnaire, the higher the score indicating a poorer quality of life. The maximum length of follow-up was 36 months. RESULTS: Twenty patients received permanent synthetic and 20 biosynthetic mesh. There was no clinical evidence of hernia recurrence in either group in the short to medium term. Overall, 97% (39/40) patients reported an average of either no or mild symptoms (mean CCS score 17.9 of 115). Patients with a biosynthetic repair had a significant lower CCS at ≥ 18 months (p < 0.05). CONCLUSION: After VIHR, patients have low CCS scores, indicating good quality of life outcomes, in the short to medium term irrespective of the mesh used. However, biosynthetic mesh had lower CCS scores in the medium term. This may help surgeons and patients make better informed decisions about which mesh to use in their individual circumstances.

Estimating single nucleotide polymorphism associations using pedigree data: applications to breast cancer.

BACKGROUND: Pedigrees with multiple genotyped family members have been underutilised in breast cancer (BC) genetic-association studies. We developed a pedigree-based analytical framework to characterise single-nucleotide polymorphism (SNP) associations with BC risk using data from 736 BC families ascertained through multiple affected individuals. On average, eight family members had been genotyped for 24 SNPs previously associated with BC. METHODS: Breast cancer incidence was modelled on the basis of SNP effects and residual polygenic effects. Relative risk (RR) estimates were obtained by maximising the retrospective likelihood (RL) of observing the family genotypes conditional on all disease phenotypes. Models were extended to assess parent-of-origin effects (POEs). RESULTS: Thirteen SNPs were significantly associated with BC under the pedigree RL approach. This approach yielded estimates consistent with those from large population-based studies. Logistic regression models ignoring pedigree structure generally gave larger RRs and association P-values. SNP rs3817198 in LSP1, previously shown to exhibit POE, yielded maternal and paternal RR estimates that were similar to those previously reported (paternal RR=1.12 (95% confidence interval (CI): 0.99-1.27), P=0.081, one-sided P=0.04; maternal RR=0.94 (95% CI: 0.84-1.06), P=0.33). No other SNP exhibited POE. CONCLUSION: Our pedigree-based methods provide a valuable and efficient tool for characterising genetic associations with BC risk or other diseases and can complement population-based studies.

Medical and Psychiatric Risk Factors for Dementia in Veterans with and without Traumatic Brain Injury (TBI): A Nationwide Cohort Study.

BACKGROUND: Traumatic brain injury (TBI) is a risk factor for dementia and is common, especially among Veterans. It is unknown whether TBI exposure moderates the effect of other common medical/psychiatric comorbidities that are also risk factors for dementia. If treatable or preventable risk factors have a different impact on TBI-exposed Veterans, then this may have important public health implications for dementia prevention. OBJECTIVES: Determine prevalence of common medical/psychiatric comorbidities and associated risk of dementia in Veterans with versus without TBI. DESIGN: Observational cohort. SETTING: Nationwide Veterans Health Administrative data 2001-2019. PARTICIPANTS: After excluding baseline dementia, Veterans age ≥55 years with TBI (N=95,139) were age/sex/race-matched 1:2 with Veterans without TBI (N=190,278). MEASUREMENTS: We compared prevalence of hypertension, coronary artery disease (CAD), diabetes, cerebrovascular disease (CVD), epilepsy, depression, and post-traumatic stress disorder (PTSD) among Veterans with and without TBI. We calculated risk of incident dementia associated with each comorbidity using multivariable hazard ratios (HR) with Fine-Grey competing risk of death adjusted for baseline demographics. We estimated population attributable fraction (PAF) of dementia due to each comorbidity among Veterans with versus without TBI. RESULTS: Prevalence of all comorbidities were significantly more prevalent (5.7% to 21.5% higher) among Veterans compared to those without TBI. All comorbidities were associated with increased risk of dementia in both groups. There were significant interactions between comorbidities and TBI in which HRs were slightly lower among Veterans with TBI (adjusted HRs 1.08-1.37) compared to those without TBI (adjusted HRs 1.12-2.13). Nevertheless, PAFs for dementia due to depression, hypertension, CAD, CVD, and epilepsy were slightly higher in Veterans with TBI due to their high prevalence in this group. CONCLUSIONS: Targeting depression, hypertension, CAD, CVD, and epilepsy may be especially important for dementia risk reduction among Veterans with TBI.

Human pelvis injury risk curves from underbody blast impact.

INTRODUCTION: Underbody blast loading can result in injuries to the pelvis and the lumbosacral spine. The purpose of this study was to determine human tolerance in this region based on survival analysis. METHODS: Twenty-six unembalmed postmortem human surrogate lumbopelvic complexes were procured and pretest medical images were obtained. They were fixed in polymethylmethacrylate at the cranial end and a six-axis load cell was attached. The specimens were aligned in a seated soldier posture. Impacts were applied to the pelvis using a custom vertical accelerator. The experimental design consisted of non-injury and injury tests. Pretest and post-test X-rays and palpation were done following non-injury test, and after injury test medical imaging and gross dissections were done. Injuries were scored using the Abbreviated Injury Scale (AIS). Axial and resultant forces were used to develop human injury probability curves (HIPCs) at AIS 3+ and AIS 4 severities using survival analysis. Then ±95% CI was computed using the delta method, normalised CI size was obtained, and the quality of the injury risk curves was assigned adjectival ratings. RESULTS: At the 50% probability level, the resultant and axial forces at the AIS 3+ level were 6.6 kN and 5.9 kN, and at the AIS 4 level these were 8.4 kN and 7.5 kN, respectively. Individual injury risk curves along with ±95% CIs are presented in the paper. Increased injury severity increased the HIPC metrics. Curve qualities were in the good and fair ranges for axial and shear forces at all probability levels and for both injury severities. CONCLUSIONS: This is the first study to develop axial and resultant force-based HIPCs defining human tolerance to injuries to the pelvis from vertical impacts using parametric survival analysis. Data can be used to advance military safety under vertical loading to the seated pelvis.

Management of purpura fulminans skin loss at a regional burns centre: Sixteen-year experience.

INTRODUCTION: Purpura fulminans (PF) is a rare syndrome of cutaneous purpura which is the consequence of severe circulatory shock causing intravascular thrombosis, haemorrhagic necrosis, and consequent tissue loss. The aim of this study was to present our 16-year experience of managing PF in a regional burns centre. METHODS: We performed a single-centre retrospective case series of all patients admitted to the St Andrews Burns Centre at Broomfield Hospital, Chelmsford, Essex, UK, between June 2006 and July 2022 with a diagnosis of PF. Data were extracted by retrospectively searching hospital case notes. RESULTS: Thirteen individuals were identified [five children (mean age 5, range 1-14) and eight adults (mean age 39, range 24-54)]. The total body surface area of cutaneous necrosis ranged from 5% to 80%, with a mean of 27.2%. Patients were treated with an established surgical sequence of total wound debridement and immediate coverage with a cadaveric allograft, followed by staged wound autografting. The mean time from disease onset to wound autografting was 37.3 days (range 20-64 days). Eight individuals (61.6%) required major amputation of at least one limb (proximal to the ankle or wrist joint). Only one mortality (of 80% total body surface area skin loss) was observed in the identified cohort. CONCLUSIONS: The large body surface areas often involved in PF cases make management of these wounds well suited for burns centres, wherein established facilities and multidisciplinary teams exist that are familiar with managing large cutaneous burns. We provide a suggested algorithm to aid the management of PF.

Nonlinear Weighting Ensemble Learning Model to Diagnose Parkinson's Disease Using Multimodal Data.

Parkinson's Disease (PD) is the second most prevalent neurodegenerative disorder among adults. Although its triggers are still not clear, they may be due to a combination of different types of biomarkers measured through medical imaging, metabolomics, proteomics or genetics, among others. In this context, we have proposed a Computer-Aided Diagnosis (CAD) system that combines structural and functional imaging data from subjects in Parkinson's Progression Markers Initiative dataset by means of an Ensemble Learning methodology trained to identify and penalize input sources with low classification rates and/ or high-variability. This proposal improves results published in recent years and provides an accurate solution not only from the point of view of image preprocessing (including a comparison between different intensity preservation techniques), but also in terms of dimensionality reduction methods (Isomap). In addition, we have also introduced a bagging classification schema for scenarios with unbalanced data. As shown by our results, the CAD proposal is able to detect PD with [Formula: see text] of balanced accuracy, and opens up the possibility of combining any number of input data sources relevant for PD.

Overcoming the coupled climate and biodiversity crises and their societal impacts.

Earth's biodiversity and human societies face pollution, overconsumption of natural resources, urbanization, demographic shifts, social and economic inequalities, and habitat loss, many of which are exacerbated by climate change. Here, we review links among climate, biodiversity, and society and develop a roadmap toward sustainability. These include limiting warming to 1.5°C and effectively conserving and restoring functional ecosystems on 30 to 50% of land, freshwater, and ocean "scapes." We envision a mosaic of interconnected protected and shared spaces, including intensively used spaces, to strengthen self-sustaining biodiversity, the capacity of people and nature to adapt to and mitigate climate change, and nature's contributions to people. Fostering interlinked human, ecosystem, and planetary health for a livable future urgently requires bold implementation of transformative policy interventions through interconnected institutions, governance, and social systems from local to global levels.

Unravelling modifiers of breast and ovarian cancer risk for BRCA1 and BRCA2 mutation carriers: update on genetic modifiers.

Pathogenic mutations in the tumour suppressor genes BRCA1 and BRCA2 confer increased risks for breast and ovarian cancer and account for approximately 15% of the excess familial risk of breast cancer amongst first-degree relatives of patients with breast cancer. There is considerable evidence indicating that these risks vary by other genetic and environmental factors clustering in families. In the past few years, based on the availability of genome-wide association data and samples from large collaborative studies, several common alleles have been found to modify breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. These common alleles explain a small proportion of the genetic variability in breast or ovarian cancer risk for mutation carriers, suggesting more modifiers remain to be identified. We review the so far identified genetic modifiers of breast and ovarian cancer risk and consider the implications for risk prediction. BRCA1 and BRCA2 mutation carriers could be some of the first to benefit from clinical applications of common variants identified through genome-wide association studies. However, to be able to provide more individualized risk estimates, it will be important to understand how the associations vary with different tumour characteristics and their interactions with other genetic and environmental modifiers.

Field reversed configuration confinement enhancement through edge biasing and neutral beam injection.

Field reversed configurations (FRCs) with high confinement are obtained in the C-2 device by combining plasma gun edge biasing and neutral beam injection. The plasma gun creates an inward radial electric field that counters the usual FRC spin-up. The n = 2 rotational instability is stabilized without applying quadrupole magnetic fields. The FRCs are nearly axisymmetric, which enables fast ion confinement. The plasma gun also produces E × B shear in the FRC edge layer, which may explain the observed improved particle transport. The FRC confinement times are improved by factors 2 to 4, and the plasma lifetimes are extended from 1 to up to 4 ms.

Cell and molecular biology of the spiny dogfish Squalus acanthias and little skate Leucoraja erinacea: insights from in vitro cultured cells.

Two of the most commonly used elasmobranch experimental model species are the spiny dogfish Squalus acanthias and the little skate Leucoraja erinacea. Comparative biology and genomics with these species have provided useful information in physiology, pharmacology, toxicology, immunology, evolutionary developmental biology and genetics. A wealth of information has been obtained using in vitro approaches to study isolated cells and tissues from these organisms under circumstances in which the extracellular environment can be controlled. In addition to classical work with primary cell cultures, continuously proliferating cell lines have been derived recently, representing the first cell lines from cartilaginous fishes. These lines have proved to be valuable tools with which to explore functional genomic and biological questions and to test hypotheses at the molecular level. In genomic experiments, complementary (c)DNA libraries have been constructed, and c. 8000 unique transcripts identified, with over 3000 representing previously unknown gene sequences. A sub-set of messenger (m)RNAs has been detected for which the 3' untranslated regions show elements that are remarkably well conserved evolutionarily, representing novel, potentially regulatory gene sequences. The cell culture systems provide physiologically valid tools to study functional roles of these sequences and other aspects of elasmobranch molecular cell biology and physiology. Information derived from the use of in vitro cell cultures is valuable in revealing gene diversity and information for genomic sequence assembly, as well as for identification of new genes and molecular markers, construction of gene-array probes and acquisition of full-length cDNA sequences.