Subcutaneous immunoglobulin replacement therapy in patients with immunodeficiencies - impact of drug packaging and administration method on patient reported outcomes.

BACKGROUND: Here, the perspective of patients with primary and secondary immunodeficiency receiving subcutaneous immunoglobulin (SCIg) via introductory smaller size pre-filled syringes (PFS) or vials were compared. METHODS: An online survey was conducted in Canada by the Association des Patients Immunodéficients du Québec (APIQ) (10/2020-03/2021). Survey questions included: reasons for choosing SCIg packaging and administration methods, training experiences, infusion characteristics, and switching methods. The survey captured structured patient-reported outcomes: treatment satisfaction and its sub-domains, symptom state, general health perception, and physical and mental function. Respondents using PFS were compared with vial users, overall and stratified by their administration method (pump or manual push). RESULTS: Of the 132 total respondents, 66 respondents used vials, with 38 using a pump and 28 using manual push. PFS (5 and 10 mL sizes) were being used by 120 respondents, with 38 using a pump and 82 using manual push. PFS users were associated with a 17% lower median (interquartile range) SCIg dose (10 [8, 12] vs. 12 [9, 16] g/week, respectively), a significantly shorter infusion preparation time (15 [10, 20] vs. 15 [10, 30] mins, respectively), and a trend for shorter length of infusion (60 [35, 90] vs. 70 [48, 90] mins, respectively) compared with those on vials. Patient-reported treatment satisfaction scores were overall similar between vial and PFS users (including on the domains of effectiveness and convenience), except for a higher score for vials over PFS on the domain of global satisfaction (p=0.02). CONCLUSIONS: Consistent with prescribing that reflects a recognition of less wastage, PFS users were associated with a significantly lower SCIg dose compared with vial users. PFS users were also associated with shorter pre-infusion times, reflecting simpler administration mechanics compared with vial users. Higher global satisfaction with treatment among vial users compared with PFS users was consistent with users being limited to smaller PFS size options in Canada during the study period. Patient experience on PFS is expected to improve with the introduction of larger PFS sizes. Overall, treatment satisfaction for SCIg remains consistently high with the introduction of PFS packaging compared with vials.

Novel methods for monitoring low chlorophyll-a concentrations in the large, oligotrophic Lake Malawi/Nyasa/Niassa.

The use of remote sensing for monitoring chlorophyll-a (chla) and modelling eutrophication has advanced over the last decades. Although the application of the technology has proven successful in ocean ecosystems, there is a need to monitor chla concentrations in large, nutrient-poor inland water bodies. The main objective of this study was to explore the utility of publicly available remotely sensed Sentinel-2 (S2) imagery to quantify chla concentrations in the nutrient-deficient Lake Malawi/Niassa/Nyasa (LMNN). A secondary objective was to compare the S2 derived chla with the Global Change Observation Mission-Climate (GCOM-C) chla product that provides uninterrupted data throughout the year. In situ chla data (n = 76) from upper, middle and lower sections of LMNN served as a reference to produce remote sensing-based quantification. The line-height approach method built on color index, was applied for chla concentrations below 0.25 mg/m3. Moderate Resolution Imaging Spectroradiometer 3-band Ocean Color (MODIS-OC3) - was adopted when chla concentration exceeded 0.35 mg/m3. The MODIS-OC3 algorithm had generic model coefficients that were calibrated for each in situ sample by using GCOM-C Level 3 chla product. A weighted sum of the two algorithms was applied for chla concentrations that fell between 0.25 and 0.35 mg/m3. The above methods were then applied to the S2 data to estimate chla at each pixel. S2 showed a promising accuracy in distinguishing chla levels (MSE = 0.18) although the chla range in the lake was relatively narrow, particularly using the locally calibrated coefficients of the OC3 algorithm. Chla distribution maps produced from the S2 data revealed limited spatial variation across the LMNN with higher concentrations identified in the coastal areas. S2-derived chla and GCOM-C chla comparison showed fairly good similarity between the two datasets (MSE = 0.205). Accepting this similarity, monthly chla dynamics of the lake was profiled using the temporally reliable GCOM-C data that showed oligotrophic conditions (1.7 mg/m3 to 3.2 mg/m3) in most parts of the lake throughout the year. The study's findings advance the potential for both remote sensing approaches to provide vital information at the required spatial and temporal resolution for evidence-based policymaking and proactive environmental management in an otherwise very data deficient region.

Robertsonian Fusion and Centromere Repositioning Contributed to the Formation of Satellite-free Centromeres During the Evolution of Zebras.

Centromeres are epigenetically specified by the histone H3 variant CENP-A and typically associated with highly repetitive satellite DNA. We previously discovered natural satellite-free neocentromeres in Equus caballus and Equus asinus. Here, through ChIP-seq with an anti-CENP-A antibody, we found an extraordinarily high number of centromeres lacking satellite DNA in the zebras Equus burchelli (15 of 22) and Equus grevyi (13 of 23), demonstrating that the absence of satellite DNA at the majority of centromeres is compatible with genome stability and species survival and challenging the role of satellite DNA in centromere function. Nine satellite-free centromeres are shared between the two species in agreement with their recent separation. We assembled all centromeric regions and improved the reference genome of E. burchelli. Sequence analysis of the CENP-A binding domains revealed that they are LINE-1 and AT-rich with four of them showing DNA amplification. In the two zebras, satellite-free centromeres emerged from centromere repositioning or following Robertsonian fusion. In five chromosomes, the centromeric function arose near the fusion points, which are located within regions marked by traces of ancestral pericentromeric sequences. Therefore, besides centromere repositioning, Robertsonian fusions are an important source of satellite-free centromeres during evolution. Finally, in one case, a satellite-free centromere was seeded on an inversion breakpoint. At 11 chromosomes, whose primary constrictions seemed to be associated with satellite repeats by cytogenetic analysis, satellite-free neocentromeres were instead located near the ancestral inactivated satellite-based centromeres; therefore, the centromeric function has shifted away from a satellite repeat containing locus to a satellite-free new position.

A Satellite-Free Centromere in Equus przewalskii Chromosome 10.

In mammals, centromeres are epigenetically specified by the histone H3 variant CENP-A and are typically associated with satellite DNA. We previously described the first example of a natural satellite-free centromere on Equus caballus chromosome 11 (ECA11) and, subsequently, on several chromosomes in other species of the genus Equus. We discovered that these satellite-free neocentromeres arose recently during evolution through centromere repositioning and/or chromosomal fusion, after inactivation of the ancestral centromere, where, in many cases, blocks of satellite sequences were maintained. Here, we investigated by FISH the chromosomal distribution of satellite DNA families in Equus przewalskii (EPR), demonstrating a good degree of conservation of the localization of the major horse satellite families 37cen and 2PI with the domestic horse. Moreover, we demonstrated, by ChIP-seq, that 37cen is the satellite bound by CENP-A and that the centromere of EPR10, the ortholog of ECA11, is devoid of satellite sequences. Our results confirm that these two species are closely related and that the event of centromere repositioning which gave rise to EPR10/ECA11 centromeres occurred in the common ancestor, before the separation of the two horse lineages.

Molecular Dynamics and Evolution of Centromeres in the Genus Equus.

The centromere is the chromosomal locus essential for proper chromosome segregation. While the centromeric function is well conserved and epigenetically specified, centromeric DNA sequences are typically composed of satellite DNA and represent the most rapidly evolving sequences in eukaryotic genomes. The presence of satellite sequences at centromeres hampered the comprehensive molecular analysis of these enigmatic loci. The discovery of functional centromeres completely devoid of satellite repetitions and fixed in some animal and plant species represented a turning point in centromere biology, definitively proving the epigenetic nature of the centromere. The first satellite-free centromere, fixed in a vertebrate species, was discovered in the horse. Later, an extraordinary number of satellite-free neocentromeres had been discovered in other species of the genus Equus, which remains the only mammalian genus with numerous satellite-free centromeres described thus far. These neocentromeres arose recently during evolution and are caught in a stage of incomplete maturation. Their presence made the equids a unique model for investigating, at molecular level, the minimal requirements for centromere seeding and evolution. This model system provided new insights on how centromeres are established and transmitted to the progeny and on the role of satellite DNA in different aspects of centromere biology.

Assessing the effect of sustainable land management on improving water security in the Blue Nile Highlands: a paired catchment approach.

The Blue Nile Highlands, Ethiopia, has been experiencing serious land degradation, menacing water security, and then human well-being. However, sustainable land management (SLM) may be the way to curb land degradation and improve water security. Therefore, in order to assess benefits after a 5-year catchment restoration effort, we conducted a paired-catchment study to investigate runoff and soil moisture dynamics. First and second catchments were used as control and treated, respectively. After comparing observations gathered from four sites within each of the study catchments, we found that implementing SLM reduced runoff curve numbers by -13.9 to -21.6 units and increased soil moisture storage by 15.6 to 800%, then promoting rapid recovery of the hydrologic functionality of the natural landscapes. We conclude that SLM initiatives can greatly improve water security in the drought-prone Blue Nile Highlands.

Birth, evolution, and transmission of satellite-free mammalian centromeric domains.

Mammalian centromeres are associated with highly repetitive DNA (satellite DNA), which has so far hindered molecular analysis of this chromatin domain. Centromeres are epigenetically specified, and binding of the CENPA protein is their main determinant. In previous work, we described the first example of a natural satellite-free centromere on Equus caballus Chromosome 11. Here, we investigated the satellite-free centromeres of Equus asinus by using ChIP-seq with anti-CENPA antibodies. We identified an extraordinarily high number of centromeres lacking satellite DNA (16 of 31). All of them lay in LINE- and AT-rich regions. A subset of these centromeres is associated with DNA amplification. The location of CENPA binding domains can vary in different individuals, giving rise to epialleles. The analysis of epiallele transmission in hybrids (three mules and one hinny) showed that centromeric domains are inherited as Mendelian traits, but their position can slide in one generation. Conversely, centromere location is stable during mitotic propagation of cultured cells. Our results demonstrate that the presence of more than half of centromeres void of satellite DNA is compatible with genome stability and species survival. The presence of amplified DNA at some centromeres suggests that these arrays may represent an intermediate stage toward satellite DNA formation during evolution. The fact that CENPA binding domains can move within relatively restricted regions (a few hundred kilobases) suggests that the centromeric function is physically limited by epigenetic boundaries.

Telomeric-Like Repeats Flanked by Sequences Retrotranscribed from the Telomerase RNA Inserted at DNA Double-Strand Break Sites during Vertebrate Genome Evolution.

Interstitial telomeric sequences (ITSs) are stretches of telomeric-like repeats located at internal chromosomal sites. We previously demonstrated that ITSs have been inserted during the repair of DNA double-strand breaks in the course of evolution and that some rodent ITSs, called TERC-ITSs, are flanked by fragments retrotranscribed from the telomerase RNA component (TERC). In this work, we carried out an extensive search of TERC-ITSs in 30 vertebrate genomes and identified 41 such loci in 22 species, including in humans and other primates. The fragment retrotranscribed from the TERC RNA varies in different lineages and its sequence seems to be related to the organization of TERC. Through comparative analysis of TERC-ITSs with orthologous empty loci, we demonstrated that, at each locus, the TERC-like sequence and the ITS have been inserted in one step in the course of evolution. Our findings suggest that telomerase participated in a peculiar pathway of DNA double-strand break repair involving retrotranscription of its RNA component and that this mechanism may be active in all vertebrate species. These results add new evidence to the hypothesis that RNA-templated DNA repair mechanisms are active in vertebrate cells.

Evaluating the data quality of the Gazepoint GP3 low-cost eye tracker when used independently by study participants.

The portability of low-cost eye trackers makes them attractive for research outside of the laboratory. Such research may require independent eye-tracker use. The present work compared the data quality of the Gazepoint GP3 when used independently by research participants with expert eye-tracking users. Twenty participants completed a training and a testing session 1 week apart. At training visits, participants were taught how to set up and use eye-tracking hardware and software and how to complete two tasks: a calibration task to measure accuracy and precision, as well as a visual search task to assess target fixations. At the testing session, participants set up the Gazepoint eye tracker and completed the two tasks without assistance. Participant accuracy and precision and visual search performance were compared to values obtained from two expert eye-tracking users. Additionally, the eye-tracker sampling rate, which is sensitive to factors such as head motion, was assessed in both participants and the expert users. Participant accuracy and precision closely approximated expert user values. Participant target fixations were detected with a 92.5% sensitivity and 76.8% specificity, closely mirroring expert user sensitivity and specificity. The sampling rate distribution was also similar between the participants and expert user (the means of those distributions were 16.99 ± 3.0 ms and 16.43 ± 2.3 ms, respectively). When used independently, data quality obtained from a low-cost, portable eye-tracking setup closely approximated values obtained from an expert user and was adequate enough to be a feasible option for some studies that require independent use by study participants.

Efficiency of microvascular free flap reconstructive surgery: An observational study.

OBJECTIVE: We aimed to assess operative workflow and efficiency in microvascular free flaps via a direct observational study based on Lean principles of quality improvement (QI). METHODS: Observers monitored the workflow of twenty-three free flaps. Pre-operative preparation and surgical duration was recorded with supplemental data provided from our institution's surgical tracking database. Traffic patterns of operating room (OR) staff were documented as "entries" and "exits" from the OR and classified by role and the reason that the entry or exit was required. Patient data was obtained via chart review. RESULTS: The mean surgical time was 9.0 h. Approximately 20% of OR time was dedicated to the pre-incision process, averaging 1.6 h per case. One third of entries and exits occurred during this period. In total, 180.2 surgical hours were observed during which 6215 "entries" and "exits" occurred. The mean number of entries and exits per case was 270; the most common reasons were supplies and communication. No association was observed between elapsed surgical time or total number of entries and exits with post-operative infection rates. CONCLUSION: Comprehensive observational workflow studies of free flaps are challenging to execute due to lengthy procedure times. At our high-volume institution, a significant portion of OR time is devoted to the pre-incision period, largely due to inadequate supply availability and pre-operative communication. These findings will serve as a foundation for QI interventions at our institution, while our observational model provides a broadly applicable framework for assessing surgical efficiency.

Insertion of Telomeric Repeats in the Human and Horse Genomes: An Evolutionary Perspective.

Interstitial telomeric sequences (ITSs) are short stretches of telomeric-like repeats (TTAGGG)n at nonterminal chromosomal sites. We previously demonstrated that, in the genomes of primates and rodents, ITSs were inserted during the repair of DNA double-strand breaks. These conclusions were derived from sequence comparisons of ITS-containing loci and ITS-less orthologous loci in different species. To our knowledge, insertion polymorphism of ITSs, i.e., the presence of an ITS-containing allele and an ITS-less allele in the same species, has not been described. In this work, we carried out a genome-wide analysis of 2504 human genomic sequences retrieved from the 1000 Genomes Project and a PCR-based analysis of 209 human DNA samples. In spite of the large number of individual genomes analyzed we did not find any evidence of insertion polymorphism in the human population. On the contrary, the analysis of ITS loci in the genome of a single horse individual, the reference genome, allowed us to identify five heterozygous ITS loci, suggesting that insertion polymorphism of ITSs is an important source of genetic variability in this species. Finally, following a comparative sequence analysis of horse ITSs and of their orthologous empty loci in other Perissodactyla, we propose models for the mechanism of ITS insertion during the evolution of this order.

Tracking conservation effectiveness in the Vhembe Biosphere Reserve in South Africa using Landsat imagery.

Biosphere reserves (BRs) seek to reconcile a sustainable relationship between human welfare and environmental integrity by adopting a landscape model that distinguishes between three interdependent management zones (core, buffer, transition). Considering the increasing human influence on landscapes in BRs, the tracking land use-land cover (LULC) dynamics is crucial for the development and planning of efficient management strategies for specific management zone. This study aimed at (i) assessing biodiversity protection around the core zones to highlight the threats facing the core zones and (ii) tracking the effect of the proclamation of the Vhembe Biosphere Reserve (VBR) on the LULC dynamics in the management zones through spatio-temporal analysis using Landsat imagery acquired from1999 to 2018. Six LULC categories (water body, forest/bush, shrubs/grass, agricultural land, bare soil, and built-up/mines) were identified and mapped using the support vector machine (SVM) classification to address both objectives. Assessment of threats around the core zones using artificial buffers (0-5, 10-15, and 15-20 km radius) created around them showed agricultural activities in the most immediate buffers (0-5 km radius). The LULC dynamics showed vegetation increase in all the management zones evidenced by the reduction of bare soil as well shrub/grass lands, and by the corresponding increase in foliage-richer forest/bush lands since the proclamation of the reserve in 2009. The findings might signify a positive outcome of vegetation increase as a consequence of the proclamation of the VBR. However, firmer conservation measures must be adopted and priority must be given to the arrangement of the management zones to strengthen biodiversity protection in the core zone.

Preserving the tree of life of the fish family Cyprinidae in Africa in the face of the ongoing extinction crisis 1.

Our understanding of how the phylogenetic tree of fishes might be affected by the ongoing extinction risk is poor. This is due to the unavailability of comprehensive DNA data, especially for many African lineages. In addition, the ongoing taxonomic confusion within some lineages, e.g., Cyprinidae, makes it difficult to contribute to the debate on how the fish tree of life might be shaped by extinction. Here, we combine COI sequences and taxonomic information to assemble a fully sampled phylogeny of the African Cyprinidae and investigate whether we might lose more phylogenetic diversity (PD) than expected if currently threatened species go extinct. We found evidence for phylogenetic signal in extinction risk, suggesting that some lineages might be at higher risk than others. Based on simulated extinctions, we found that the loss of all threatened species, which approximates 37% of total PD, would lead to a greater loss of PD than expected, although highly evolutionarily distinct species are not particularly at risk. Pending the reconstruction of an improved multi-gene phylogeny, our results suggest that prioritizing high-EDGE species (evolutionary distinct and globally endangered species) in conservation programmes, particularly in some geographic regions, would contribute significantly to safeguarding the tree of life of the African Cyprinidae.

Understanding Chronic Aggression and Its Treatment in Children and Adolescents.

PURPOSE OF REVIEW: Youth aggression is common and has a significant burden on individuals, families, and society. However, its treatment is often a challenge for clinicians. Thus, this review will examine the current understanding of youth aggression, conceptualize aggression as a symptom rather than its own disorder, and provide an overview of treatment strategies. RECENT FINDINGS: Youth aggression is associated with complex genetic, neurobiological, and environmental risks. Prevention strategies are of the utmost importance for at-risk families and youth. Psychosocial interventions are the first line treatment. But if not fully effective, then pharmacologic interventions-including psychostimulants, alpha-2 agonists, atomoxetine, and risperidone-have shown benefits. Other medications, such as SSRIs, can be useful in certain scenarios. It is important to conceptualize youth aggression as being a trans-diagnostic symptom in psychopathology. Determining the underlying cause of aggression will help to guide treatment.

Telomere length is reflected by plumage coloration and predicts seasonal reproductive success in the barn swallow.

Individuals differ in realized fitness but the genetic/phenotypic traits that underpin such variation are often unknown. Telomere dynamics may be a major source of variation in fitness traits because physiological telomere shortening depends on environmental and genetic factors and may impair individual performance. Here, we showed that, in a population of a socially monogamous, biparental passerine bird, the barn swallow (Hirundo rustica), breeding in northern Italy, telomere length (TL) of both adult males and females positively correlated with seasonal reproductive and fledging success, as expected because long telomeres are supposed to boost performance. Telomere length was correlated with sexually dimorphic coloration in both sexes, showing for the first time in any species that coloration reliably reflects TL and may mediate mutual mate choice, leading to the observed positive assortative mating for TL in the barn swallow. Thus, TL appears to be associated with variation in a major fitness trait and may be an ultimate target of mate choice, as individuals of both sexes can use coloration to adaptively choose high-quality mates that possess long telomeres.

Leptin resistance elicits depressive-like behaviors in rats.

There is a growing appreciation that the complications of obesity extend to the central nervous system (CNS) and include increased risk for development of neuropsychiatric co-morbidities such as depressive illness. The neurological consequences of obesity may develop as a continuum and involve a progression of pathological features which is initiated by leptin resistance. Leptin resistance is a hallmark feature of obesity, but it is unknown whether leptin resistance or blockage of leptin action is casually linked to the neurological changes which underlie depressive-like phenotypes. Accordingly, the aim of the current study was to examine whether chronic administration of a pegylated leptin receptor antagonist (Peg-LRA) elicits depressive-like behaviors in adult male rats. Peg-LRA administration resulted in endocrine and metabolic features that are characteristic of an obesity phenotype. Peg-LRA rats also exhibited increased immobility in the forced swim test, depressive-like behaviors that were accompanied by indices of peripheral inflammation. These results demonstrate that leptin resistance elicits an obesity phenotype that is characterized by peripheral immune changes and depressive-like behaviors in rats, supporting the concept that co-morbid obesity and depressive illness develop as a continuum resulting from changes in the peripheral endocrine and metabolic milieu.

Repair or Replacement of Restorations: A Prospective cohort study by dentists in The National Dental Practice-Based Research Network.

BACKGROUND: A prospective cohort study that included dentists in The National Dental Practice-Based Research Network was conducted to quantify 12-month failures of restorations that were repaired or replaced at baseline. The study tested the hypothesis that no significant differences exist in failure percentages between repaired and replaced restorations after 12 months. It also tested the hypothesis that certain dentist, patient, and restoration characteristics are significantly associated with the incidence of restoration failure. METHODS: Dentists recorded data for 50 or more consecutive defective restorations. The restorations that were either - repaired or replaced were recalled after 12 months and characterized for developing defects. RESULTS: Dentists (N = 195) recorded data on 5,889 restorations; 378 restorations required additional treatment (74 repaired, 171 replaced, 84 teeth received endodontic treatment, and 49 were extracted). Multivariable logistic regression analysis indicated that additional treatment was more likely to occur if the original restoration had been repaired (7%) compared with replaced (5%) (odds ratio [OR], 1.6; P < .001; 95% confidence interval [CI], 1.2-2.1), if a molar was restored (7%) compared with premolars or anterior teeth (5% and 6%, respectively) (OR, 1.4; P = .010; 95% CI, 1.1-1.7), and if the primary reason was a fracture (8%) compared with other reasons (6%) (OR, 1.3; P = .033; 95% CI, 1.1-1.6). CONCLUSIONS: An additional treatment was more likely to occur within the first year if the original restoration had been repaired (7%) compared with being replaced (5%). However, repaired restorations were less likely to need an aggressive treatment (replacement, endodontic treatment, or extraction) than replaced restorations. PRACTICAL IMPLICATIONS: One year after repair or replacement of a defective restoration, the failure rate was low. However, repaired restorations were less likely to need an aggressive treatment than replaced restorations.

Particle-Tracking Microrheology Using Micro-Optical Coherence Tomography.

Clinical manifestations of cystic fibrosis (CF) result from an increase in the viscosity of the mucus secreted by epithelial cells that line the airways. Particle-tracking microrheology (PTM) is a widely accepted means of determining the viscoelastic properties of CF mucus, providing an improved understanding of this disease as well as an avenue to assess the efficacies of pharmacologic therapies aimed at decreasing mucus viscosity. Among its advantages, PTM allows the measurement of small volumes, which was recently utilized for an in situ study of CF mucus formed by airway cell cultures. Typically, particle tracks are obtained from fluorescence microscopy video images, although this limits one's ability to distinguish particles by depth in a heterogeneous environment. Here, by performing PTM with high-resolution micro-optical coherence tomography (µOCT), we were able to characterize the viscoelastic properties of mucus, which enables simultaneous measurement of rheology with mucociliary transport parameters that we previously determined using µOCT. We obtained an accurate characterization of dextran solutions and observed a statistically significant difference in the viscosities of mucus secreted by normal and CF human airway cell cultures. We further characterized the effects of noise and imaging parameters on the sensitivity of µOCT-PTM by performing theoretical and numerical analyses, which show that our system can accurately quantify viscosities over the range that is characteristic of CF mucus. As a sensitive rheometry technique that requires very small fluid quantities, µOCT-PTM could also be generally applied to interrogate the viscosity of biological media such as blood or the vitreous humor of the eye in situ.

Centromere sliding on a mammalian chromosome.

The centromere directs the segregation of chromosomes during mitosis and meiosis. It is a distinct genetic locus whose identity is established through epigenetic mechanisms that depend on the deposition of centromere-specific centromere protein A (CENP-A) nucleosomes. This important chromatin domain has so far escaped comprehensive molecular analysis due to its typical association with highly repetitive satellite DNA. In previous work, we discovered that the centromere of horse chromosome 11 is completely devoid of satellite DNA; this peculiar feature makes it a unique model to dissect the molecular architecture of mammalian centromeres. Here, we exploited this native satellite-free centromere to determine the precise localization of its functional domains in five individuals: We hybridized DNA purified from chromatin immunoprecipitated with an anti CENP-A antibody to a high resolution array (ChIP-on-chip) of the region containing the primary constriction of horse chromosome 11. Strikingly, each individual exhibited a different arrangement of CENP-A binding domains. We then analysed the organization of each domain using a single nucleotide polymorphism (SNP)-based approach and single molecule analysis on chromatin fibres. Examination of the ten instances of chromosome 11 in the five individuals revealed seven distinct 'positional alleles', each one extending for about 80-160 kb, were found across a region of about 500 kb. Our results demonstrate that CENP-A binding domains are autonomous relative to the underlying DNA sequence and are characterized by positional instability causing the sliding of centromere position. We propose that this dynamic behaviour may be common in mammalian centromeres and may determine the establishment of epigenetic alleles.

An approach to develop chemical intuition for atomistic electron transport calculations using basis set rotations.

Single molecule conductance measurements are often interpreted through computational modeling, but the complexity of these calculations makes it difficult to directly link them to simpler concepts and models. Previous work has attempted to make this connection using maximally localized Wannier functions and symmetry adapted basis sets, but their use can be ambiguous and non-trivial. Starting from a Hamiltonian and overlap matrix written in a hydrogen-like basis set, we demonstrate a simple approach to obtain a new basis set that is chemically more intuitive and allows interpretation in terms of simple concepts and models. By diagonalizing the Hamiltonians corresponding to each atom in the molecule, we obtain a basis set that can be partitioned into pseudo-σ and -π and allows partitioning of the Landuaer-Büttiker transmission as well as create simple Hückel models that reproduce the key features of the full calculation. This method provides a link between complex calculations and simple concepts and models to provide intuition or extract parameters for more complex model systems.