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PubMed2026

Metadomain and metaloop genome interactions in mammalian T cells.

Recent studies have advanced understanding of chromosomal organization and its role in gene regulation, yet most analyses focus on short-range interactions (<2 Mb), limiting insight into broader architecture. The relationships between topologically associating domains (TADs), sub-TAD loops, cross-TAD interactions, and chromosomal compartmentalization remain poorly understood. Here, using high-resolution Hi-C analysis, we identify extensive multi-megabase and interchromosomal interactions (metaloops) in T lymphocytes that organize into meta-TAD associations (metadomains). These metaloops connect distal promoters and regulatory elements of genes functionally important in T cells, including Ctla4, Ikzf2, Il2ra, Ets1, and Foxo1. Reanalysis of mouse and human datasets confirms their reproducibility and dependence on superenhancers. Genome-wide clustering reveals three distinct interchromosomal hubs, including a superenhancer-enriched hub linked to T cell-specific gene activation. Integrative analysis of regulatory genomics data identifies factors associated with short- versus long-range interactions. This study introduces a broadly applicable computational framework and reveals features of T cell genome organization.

Animals↗

PubMed2005

Modification of Langmuir isotherm in solution systems--definition and utilization of concentration dependent factor.

The Langmuir isotherm, originally derived for the adsorption of gas molecules on solid surfaces, was modified to fit the adsorption isotherm of solutes onto solid surfaces in solution systems. The aim of this modification is based on the fact that direct application of the Langmuir isotherm to solution systems often leads to poor data fitting. In the present communication, it is shown that the level of data fitting to the Langmuir isotherm of literature data can be improved by a simple modification introducing a concentration dependent factor, X. The key concept of the modification lies in that the concentration of solute affects both adsorption and desorption stages. As a first approximation, we adopted a single-term polynomial for both processes of adsorption and desorption. Based on reanalysis of literature data of adsorption in solution, we confirmed that indeed the modified Langmuir isotherm more accurately describes the experimental observations. Furthermore, we proposed that the concentration dependent factor could be associated with the surface heterogeneity index that was introduced in a few other modified Langmuir isotherms. Some advantages and limitations of proposed modified Langmuir isotherm are also discussed.

Adsorption↗

PubMed2004

On the cost of syntactic ambiguity in human language comprehension: an individual differences approach.

We present an event-related brain potential (ERP) study demonstrating that high and low span readers show qualitatively different brain responses in the comprehension of ambiguous and complex linguistic stimuli. During the processing of ambiguous German sentences, low span readers showed a broadly distributed, sustained positivity, whereas high span participants showed a shorter, topographically more focused negativity. Qualitatively similar effects were observable in response to (complex) object-initial sentences. Additionally, a neural effect reflecting reanalysis in sentences disambiguated in a dispreferred way (P600) was observable only for high span readers, while the low span group showed an N400-like response. These neurophysiological findings support the notion that individual working memory capacity as measured by the reading span test influences sentence processing mechanisms and are compatible with the hypothesis that low span readers cannot effectively inhibit dispreferred readings.

Adult↗

PubMed2026

Tn125-borne blaNDM-1 is decoupled from clonal background in a transcontinental Acinetobacter baumannii ST126/KL14 lineage.

BACKGROUND/OBJECTIVES: Carbapenem-resistant A. baumannii (CRAB) is a WHO Critical Priority pathogen. The blaNDM-1-carrying ST126/KL14 lineage has been independently reported from Vietnam (2015), Malaysia (2016), the USA (2023-2026), and Costa Rica (2024). Whether these geographically distinct reports represent a single transcontinental clone and through what mechanism blaNDM-1 disseminates has not been formally tested. METHODS: We performed comprehensive whole-genome reanalysis of the Vietnamese sentinel isolate DMS06669_L1 using three nested panels (n = 19, n = 138, and n = 609 Vietnamese A. baumannii genomes) and surveyed 429 plasmids extracted from 99 NDM-1 A. baumannii genomes retrieved from NCBI Pathogen Detection. RESULTS: Four ST126/KL14 isolates share high inter-regional average nucleotide identity (ANI; 99.77-99.92%) but wide intra-clade core-SNP distances (41-731 SNPs, well above the ∼20-40-SNP range typical of single-outbreak transmission clusters) and lack a significant molecular clock, consistent with a related transcontinental lineage rather than a single recent clone. NDM-1 plasmid evolution is statistically uncorrelated with chromosomal sequence type (Spearman ρ = 0.131, P = 0.573). At 609-strain population scale, under a fragmentation-aware detection criterion, all 41 blaNDM-1-carrying Vietnamese strains also carry ISAba125, with none carrying blaNDM-1 without it (Fisher exact test; Haldane-Anscombe-corrected OR ≈2.0 × 10³, 95% CI 1.2 × 10² to 3.4 × 10⁴; P = 4.74×10⁻⁴⁸; φ = 0.79). CONCLUSIONS: The blaNDM-1 dissemination pattern in this ST126/KL14 lineage is primarily consistent with Tn125 transposition acting alongside plasmid-borne spread. Standard MLST-based surveillance is insufficient; multi-level genomic monitoring - including chromosomal and plasmid-level detection of the Tn125/ISAba125 unit - is required to track this resistance threat.

A. baumannii↗

PubMed2003

Blandowski misses out: ichthyological etiquette in 19th-century Australia.

Wilhelm Blandowski, a Prussian émigré, arrived in Australia in 1849 with hopes of exploring and documenting the natural history of this still relatively scientifically nai;ve colony. After several years travelling, surveying and mining gold, he became the first government zoologist at the infant National Museum of Victoria and was a key player in the burgeoning scientific establishment. Chosen to lead a collecting expedition to the junction of the Murray and Darling Rivers in 1856, Blandowski and his faithful companion Gerard Krefft brought back a wealth of new material, including many species of undescribed freshwater fishes. Unfortunately, Blandowski's attempts to 'honour' members of the Philosophical Institute of Victoria backfired and a scandal ensued. A disillusioned Blandowski left Australia just ten years after his arrival. A reanalysis of his descriptions of the fish and comparison with a contemporary work suggests that Blandowski deserves recognition as one of pioneers in the natural history of Australian freshwater fish. The loss of taxonomic authority for eight fish species by this energetic, imaginative, but stubborn scientist, left the way open for future workers to make their mark, whereas Blandowski's name and achievements remain obscure.

Animals↗

PubMed2005

Exploring nonlinear association between prenatal methylmercury exposure from fish consumption and child development: evaluation of the Seychelles Child Development Study nine-year data using semiparametric additive models.

Studies of the association between prenatal methylmercury exposure from maternal fish consumption and neurodevelopmental test scores in the Seychelles Child Development Study have not found adverse effects through age 9 years. The analysis for the most recent 9-year data (Lancet 361 (2003) 1686) employed conventional linear regression models. In this study we reanalyzed the same Seychelles 9-year data using semiparametric additive models with different degrees of smoothing to explore whether nonlinear effects of prenatal exposure were present. Of 21 endpoints in the linear analysis, we chose only those with a two-tailed P value less than 0.2 for the effect of prenatal exposure. Six endpoints met the criterion. A nonlinear effect was identified with the more smooth model for only one endpoint. The test for an overall effect of prenatal exposure was also significant, with a P value of 0.04, while the corresponding P value in the linear regression analysis was 0.08. The nonlinear curve appeared to be nearly flat when the level was below approximately 12 ppm in maternal hair, with a linear trend above that level, suggesting a possible adverse effect in the uppermost range of prenatal exposure included in this cohort. Because of the descriptive nature of semiparametric additive models, the P values are not precise, and certainly there are fewer data above 12 ppm. We conclude that this reanalysis supports the primary linear analysis, showing little evidence for a prenatal adverse effect.

Child↗

PubMed2006

Embryo morphology and development are dependent on the chromosomal complement.

OBJECTIVE: To analyze embryo morphology in relation to the corresponding chromosomal status, in order to evaluate the effects of aneuploidy over fragmentation, delayed cleavage, and arrested cleavage. DESIGN: Retrospective study. SETTING: Reproductive Medicine Unit, Società Italiana di Studi di Medicina della Riproduzione, Bologna, Italy. PATIENT(S): A total of 662 patients with a poor prognosis for pregnancy underwent 916 cycles of preimplantation genetic diagnosis for aneuploidy. INTERVENTION(S): The chromosomes XY, 13, 15, 16, 18, 21, and 22 were analyzed in blastomeres biopsied from day 3 embryos. MAIN OUTCOME MEASURE(S): Embryo morphology, chromosomal status of the analyzed blastomeres, and spreading and reanalysis of nontransferred embryos. RESULT(S): The incidence of chromosomal abnormalities was significantly higher in arrested or slow-cleaving embryos, and in embryos cleaving too fast, compared to embryos with eight cells at 62 hours after insemination. The presence of an uneven number of blastomeres or fragments scattered in the perivitelline space was associated with an increased incidence of chromosomal abnormalities. CONCLUSION(S): A correlation between embryo development and chromosomal complement makes the incidence of chromosomal abnormalities significantly higher in embryos dividing according to a time frame and a symmetry plan which are different from what are expected. The type of fragmentation is also related to chromosomal status, which explains why the extrusion of fragments might severely affect embryo viability.

Adult↗

PubMed2005

Validation of a male-specific, 12-locus fluorescent short tandem repeat (STR) multiplex.

Y chromosome-specific short tandem repeat (Y-STR) analysis has become another widely accepted tool for human identification. The PowerPlex Y System is a fluorescent multiplex that includes the 12 loci: DYS19, DYS385a/b, DYS389I/II, DYS390, DYS391, DYS392, DYS393, DYS437, DYS438 and DYS439. This panel of markers incorporates the 9-locus European minimal haplotype (EMH) loci recommended by the International Y-STR User Group and the 11-locus set recommended by the Scientific Working Group on DNA Analysis Methods (SWGDAM). Described here are inter-laboratory results from 17 developmental validation studies of the PowerPlex Y System and include the following results: (a) samples distributed between laboratories and commercial standards produced expected and reproducible haplotypes; (b) use of common amplification and detection instruments were successfully demonstrated; (c) full profiles were obtained with standard 30 and 32 cycle amplification protocols and cycle number (24-28 cycles) could be modified to match different substrates (such as direct amplification of FTA paper); (d) complete profiles were observed with reaction volumes from 6.25 to 50 microL; (e) minimal impact was observed with variation of enzyme concentration; (f) full haplotypes were observed with 0.5-2x primer concentrations; however, relative yield between loci varied with concentration; (g) reduction of magnesium to 1mM (1.5 mM standard) resulted in minimal amplification, while only partial loss of yield was observed with 1.25 mM magnesium; (h) decreasing the annealing temperature by 2-4 degrees C did not generate artifacts or locus dropout and most laboratories observed full amplification with the annealing temperature increased by 2 degrees C and significant locus dropout with a 4 degrees C increase in annealing temperature; (i) amplification of individual loci with primers used in the multiplex produced the same alleles as observed with the multiplex amplification; (j) all laboratories observed full amplification with >or = 125 pg of male template with partial and/or complete profiles observed using 30-62.5 pg of DNA; (k) analysis of < or = 500 ng of female DNA did not yield amplification products; (l) the minor male component of a male/female mixture was observed with < or =1200-fold excess female DNA with the majority of alleles still observed with 10,000-fold excess female; (m) male/male mixtures produced full profiles from the minor contributor with 10-20-fold excess of the major contributor; (n) average stutter for each locus; (o) precision of sizing were determined; (p) human-specificity studies displayed amplification products only with some primate samples; and (q) reanalysis of 102 non-probative casework samples from 65 cases produced results consistent with original findings and in some instances additional identification of a minor male contributor to a male/female mixture was obtained. In general, the PowerPlex Y System was shown to have the sensitivity, specificity and reliability required for forensic DNA analysis.

Animals↗

PubMed2005

Validation of male-specific, 12-locus fluorescent short tandem repeat (STR) multiplex.

Animals↗

PubMed2005

Driving under the influence of chlormethiazole.

This article describes a case of driving under the influence of the sedative-hypnotic-anticonvulsant drug chlormethiazole. The suspect, who was a physician, was driving dangerously on a busy highway and caused a traffic collision. When apprehended by the police, the man had bloodshot and glazed eyes and pupil size was enlarged. He could not answer the questions properly and his gait was unsteady. A roadside breath-alcohol screening test was positive but an evidential breath-alcohol test conducted about one hour later was below the legal limit for driving of 0.10 mg/L (10 microg/100 mL or 0.021 g/210 L). Because of the special circumstances of the traffic crash and the man's appearance and behaviour, the police suspected that drugs other than alcohol were involved and obtained a venous blood sample for toxicological analysis. The blood contained 0.23 mg/g alcohol, which is above the legal limit for driving in Sweden 0.20 mg/g (20 mg/100 mL or 0.020 g/100 mL), and codeine was also present at a therapeutic concentration of 0.02 mg/L. The conflict between the clinical signs of impairment and the toxicology report prompted a reanalysis of the blood sample with major focus on sedative-hypnotic drugs. Analysis by capillary GC-NPD identified chlormethiazole at a concentration of 5mg/L, the highest so far encountered in traffic cases in Sweden. In 13 other impaired driving cases over 10 years the mean (median) and range of concentrations of chlormethiazole were 1.6 mg/L (1.6 mg/L) and 0.3-3.3 mg/L. This case report underscores the need to consider clinical observations and the person's behaviour in relation to the toxicology report when interpreting and testifying in drug-impaired driving cases.

Accidents, Traffic↗

PubMed2005

Discrepancies between forensic identification kits explained by a laser power supply shutdown.

The occurrence of two null alleles for the same individual was suspected because of the discrepancy at two loci (vWA and THO1) between genotypes characterized by the mean of two different commercial kits. Reanalysis of the samples indicated there was no null allele, and that this abnormality was indeed related to an automatic laser power shutdown. The laser power supply was set to a value (6.4V) too close to the automatic shutdown threshold (6.0V). The alleles were undetected because of the absence of emission at the time of migration of the two alleles through the detection device. However, since no alarm is triggered in such an event, the users should monitor their laser power supply values.

Alleles↗

PubMed2024

Microduplications of ARID1A and ARID1B cause a novel clinical and epigenetic distinct BAFopathy.

PURPOSE: ARID1A/ARID1B haploinsufficiency leads to Coffin-Siris syndrome, duplications of ARID1A lead to a distinct clinical syndrome, whilst ARID1B duplications have not yet been linked to a phenotype. METHODS: We collected patients with duplications encompassing ARID1A and ARID1B duplications. RESULTS: 16 ARID1A and 13 ARID1B duplication cases were included with duplication sizes ranging from 0.1 to 1.2 Mb (1-44 genes) for ARID1A and 0.9 to 10.3 Mb (2-101 genes) for ARID1B. Both groups shared features, with ARID1A patients having more severe intellectual disability, growth delay, and congenital anomalies. DNA methylation analysis showed that ARID1A patients had a specific methylation pattern in blood, which differed from controls and from patients with ARID1A or ARID1B loss-of-function variants. ARID1B patients appeared to have a distinct methylation pattern, similar to ARID1A duplication patients, but further research is needed to validate these results. Five cases with duplications including ARID1A or ARID1B initially annotated as duplications of uncertain significance were evaluated using PhenoScore and DNA methylation reanalysis, resulting in the reclassification of 2 ARID1A and 2 ARID1B duplications as pathogenic. CONCLUSION: Our findings reveal that ARID1B duplications manifest a clinical phenotype, and ARID1A duplications have a distinct episignature that overlaps with that of ARID1B duplications, providing further evidence for a distinct and emerging BAFopathy caused by whole-gene duplication rather than haploinsufficiency.

Humans↗

PubMed2025

Sustainability in translational genomics research with undiagnosed patients: What is it, why do we need it, and how do we do it?

PURPOSE: Genomics research enrolling undiagnosed patients can provide answers for one-third of participants, and more can be diagnosed through future reanalysis. The long-term value for participants has raised questions of the sustainability of these studies, but the meaning, goals, and best practices for sustainability remain unclear. METHODS: We conducted semistructured interviews with researchers leading studies enrolling undiagnosed patients in the United States and Canada and used thematic content analysis to summarize key themes. RESULTS: Researchers lacked consensus regarding what sustainability was actually intended to sustain, variably referencing study procedures, personnel, data access, and participant recontact. However, the primary driver of sustainability was widely shared as the perceived obligation to continue to search for answers for undiagnosed participants. Proposed sustainability strategies included diversifying funding sources, developing centralized data infrastructure, and building collaborations across disciplines and institutions. Researchers also emphasized the need to address ethical concerns, to integrate research with clinical care, and for leadership from research funders to guide these efforts. CONCLUSION: Although genomics researchers perceived continued obligations to undiagnosed participants, they also lacked a shared understanding of the goals of sustainability and called for coordinated efforts to develop centralized infrastructure that integrated research and clinical care.

Humans↗

PubMed2025

Genome sequencing reveals the impact of pseudoexons in rare genetic disease.

PURPOSE: Advancements in sequencing technologies have significantly improved clinical genetic testing; yet, the diagnostic yield remains around 30% to 40%. Emerging technologies are now being deployed to address the remaining diagnostic gap. METHODS: We tested whether short-read genome sequencing could increase the diagnostic yield in individuals enrolled into the UCI-GREGoR research study, who had suspected Mendelian conditions and prior inconclusive testing. Two other collaborative research cohorts, focused on aortopathy and dilated cardiomyopathy, consisted of individuals who were undiagnosed but had not undergone harmonized prior testing. RESULTS: We sequenced 353 families (754 participants) and found a molecular diagnosis in 54 (15.3%) of them. Of these diagnoses, 55.5% were previously missed because the causative variants were in regions not originally interrogated. In 5 cases, they were deep intronic variants, all of which led to abnormal splicing and pseudoexons, as directly shown by RNA sequencing. All 5 of these variants had inconclusive spliceAI scores. In 26% of newly diagnosed cases, the causal variant could have been detected by exome sequencing reanalysis. CONCLUSION: Genome sequencing can overcome limitations of clinical genetic testing, such as the inability to call intronic variants. Our findings highlight pseudoexons as a common mechanism via which deep intronic variants cause Mendelian disease.

Humans↗

PubMed2004

[Effects of HRT on the risks of breast cancer and cardiovascular disease: the validity of the epidemiological evidence].

Publication of the findings of the Women's Health Initiative, in July 2002, the second link of the triptych made up of the Collaborative Reanalysis, in 1997, and the Women Million Study, in 2003, shortly after the WHI, seems to have tolled the knell of HRT, by claiming that women using HRT and combined therapy, have an increased risk of breast cancer and cardiovascular disease. As a result, the risk-benefit ratio would be reversed to the detriment of HRT. Over and above the legitimate questioning on the validity of these studies, such as calling into question their indisputable biases, especially the detection bias and hereby analysed in its spoiling the three randomised essays-there is the crucial question: can epidemiology make any headway in elucidating the hormonal aetiology of breast cancer? Indeed, given the low relative risks that have been observed, on the one hand, coupled with a whole set of methodological limitations, it is impossible to distinguish between bias and causation as alternative explanations for the observed associations. Above all, what emerges from this investigation is that, as far as HRT effects especially on breast cancer are concerned, epidemiological evidence only is inadequate, and collaborative research between histopathology and epidemiology is necessary.

Bias↗

PubMed2005

Diagnosis and presentation of fatal myocarditis.

The clinical presentation of myocarditis is highly variable, and histopathology is thus considered to be the cornerstone of diagnosis. We studied how accurately myocarditis was diagnosed in a series of routine autopsies and how fatal myocarditis presents clinically. All death certificates with myocarditis recorded as the underlying cause of death in Finland in 1970 to 1998 were collected retrospectively (N = 639). All cases with cardiac autopsy samples and clinical data available (n = 142; median age, 51 years) were included in this study. The cardiac samples were reexamined for the presence of myocarditis by 3 experienced independent pathologists using the Dallas criteria. The clinical data were evaluated for the presenting signs and symptoms of myocarditis. Histopathologic reanalysis showed that only 32% of the 142 subjects met the Dallas criteria for myocarditis (75% of pediatric and 28% of adult patients, P = .001). Clinicians had suspected myocarditis in only one third of the hospitalized Dallas-positive patients. Dallas-positive patients presented more often with features of myocardial infarction (26% versus 9%, P = .026) or heart failure (35% versus 10%, P = .001) than Dallas-negative subjects. The signs and symptoms of infectious disease were also more common in Dallas-positive patients (61% versus 23%, P < .001). In contrast, Dallas-negative subjects died suddenly or were found dead more frequently (68% versus 39%, P = .004). The most evident cause of death in the Dallas-negative subjects was ischemic heart disease (n = 78, 55% of all cases). Our study provides evidence that myocarditis is overdiagnosed on routine autopsies, particularly in patients who have died suddenly or are found dead. Fatal myocarditis appears to present equally often as heart failure, sudden death, or mimicking myocardial infarction.

Adolescent↗

PubMed2005

Improved treatment planning for COMS eye plaques.

PURPOSE: A recent reanalysis of the Collaborative Ocular Melanoma Study (COMS) medium tumor trial concluded that incorporating factors to account for anisotropy, line source approximation, the gold plaque, and attenuation in the Silastic seed carrier into the dose calculations resulted in a significant and consistent reduction of calculated doses to structures of interest within the eye. The authors concluded that future eye plaque dosimetry should be "performed using the most up-to-date parameters available." The reason these factors are important is attributable to the low energy (125)I radiation (approximately 28 keV) that is primarily absorbed by the photoelectric process. Photoelectric absorption is quite dependent on the atomic composition of the absorbing material. Being 40% silicon by weight, the effective atomic number of Silastic is significantly greater than that of water. Although the AAPM TG43 brachytherapy formalism inherently addresses the issues of source anisotropy and geometry, its parameter that accounts for scatter and attenuation, the radial dose function g(r), assumes that the source is immersed in infinite homogeneous water. In this work, factors are proposed for (125)I that correct for attenuation in the Silastic carrier and scatter deficits resulting from the gold plaque and nearby air. The implications of using (103)Pd seeds in COMS plaques are also discussed. METHODS AND MATERIALS: An existing TG43-based ophthalmic plaque planning system was modified to incorporate additional scatter and attenuation correction factors that better account for the path length of primary radiation in the Silastic seed carrier and the distance between the dose calculation point and the eye-air interface. RESULTS: Compared with homogeneous water, the dose-modifying effects of the Silastic and gold are greatest near the plaque surface and immediately adjacent to the plaque, while being least near the center of the eye. The calculated dose distribution surrounding a single (125)I seed centered in a COMS 20 mm plaque was found to be consistent with previously published examples that used thermoluminescent dosimetry measurements and Monte Carlo methods. For fully loaded 12 and 20 mm plaques, calculated dose to critical ocular structures ranged from 16%-50% less than would have been reported using the standard COMS dose calculation protocol. CONCLUSIONS: Treatment planning for COMS eye plaques that accurately accounts for the presence of the gold, Silastic and extraocular air is both possible and practical.

Algorithms↗

PubMed2004

Ocular torsion: rotations around the "WHY" axis.

BACKGROUND: Traditional teaching holds that there is a partial compensatory countertorsion after head tilt because the intorters in the eye on the side of the head tilt and the extorters in the contralateral eye are stimulated. This teaching is inconsistent with a number of clinical observations. METHODS: Review of existing literature, reanalysis of data from the investigator's previous experiments, and inductive and deductive reasoning were used to reconcile inconsistencies and present a theory on why torsional movements occur. RESULTS: The inconsistencies can be reconciled if one considers that during the dynamic phase of head tilt, there is an alternating series of intorsional and extorsional movements of both eyes. Each eye has slow dynamic compensatory counterrolling phases that serve as torsional "doll's-head" movements to stabilize the image during head tilt. This counterrolling is partially eliminated by a series of anticompensatory torsional saccades in the direction of head tilt, which is in contrast to traditional teaching. CONCLUSION: Dynamic compensatory counterrolling occurs during head tilt. It is largely eliminated by anticompensatory torsional saccades in the opposite direction so that by the end of head tilt only minimal static countertorsion remains. The dynamic compensatory counterrolling motion is necessary to minimize peripheral visual movement during head tilt. The elimination of most of the counterrolling by the end of head tilt is necessary to preserve convergence and stereopsis.

Convergence, Ocular↗