Scellpam: an R package/C++ library to perform parallel partitioning around medoids on scRNAseq data sets.

BACKGROUND: Partitioning around medoids (PAM) is one of the most widely used and successful clustering method in many fields. One of its key advantages is that it only requires a distance or a dissimilarity between the individuals, and the fact that cluster centers are actual points in the data set means they can be taken as reliable representatives of their classes. However, its wider application is hampered by the large amount of memory needed to store the distance matrix (quadratic on the number of individuals) and also by the high computational cost of computing such distance matrix and, less importantly, by the cost of the clustering algorithm itself. RESULTS: Therefore, new software has been provided that addresses these issues. This software, provided under GPL license and usable as either an R package or a C++ library, calculates in parallel the distance matrix for different distances/dissimilarities ([Formula: see text], [Formula: see text], Pearson, cosine and weighted Euclidean) and also implements a parallel fast version of PAM (FASTPAM1) using any data type to reduce memory usage. Moreover, the parallel implementation uses all the cores available in modern computers which greatly reduces the execution time. Besides its general application, the software is especially useful for processing data of single cell experiments. It has been tested in problems including clustering of single cell experiments with up to 289,000 cells with the expression of about 29,000 genes per cell. CONCLUSIONS: Comparisons with other current packages in terms of execution time have been made. The method greatly outperforms the available R packages for distance matrix calculation and also improves the packages that implement the PAM itself. The software is available as an R package at https://CRAN.R-project.org/package=scellpam and as C++ libraries at https://github.com/JdMDE/jmatlib and https://github.com/JdMDE/ppamlib The package is useful for single cell RNA-seq studies but it is also applicable in other contexts where clustering of large data sets is required.

A cell abundance analysis based on efficient PAM clustering for a better understanding of the dynamics of endometrial remodelling.

BACKGROUND: Single-cell RNA sequencing (scRNA-seq) is a powerful tool for investigating cell abundance changes during tissue regeneration and remodeling processes. Differential cell abundance supports the initial clustering of all cells; then, the number of cells per cluster and sample are evaluated, and the dependence of these counts concerning the phenotypic covariates of the samples is studied. Analysis heavily depends on the clustering method. Partitioning Around Medoids (PAM or k-medoids) represents a well-established clustering procedure that leverages the downstream interpretation of clusters by pinpointing real individuals in the dataset as cluster centers (medoids) without reducing dimensions. Of note, PAM suffers from high computational costs and memory requirements. RESULTS: This paper proposes a method for differential abundance analysis using PAM as a clustering method and negative binomial regression as a statistical model to relate covariates to cluster/cell counts. We used this approach to study the differential cell abundance of human endometrial cell types throughout the natural secretory phase of the menstrual cycle. We developed a new R package -scellpam-, that incorporates an efficient parallel C++ implementation of PAM, and applied this package in this study. We compared the PAM-BS clustering method with other methods and evaluated both the computational aspects of its implementation and the quality of the classifications obtained using distinct published datasets with known subpopulations that demonstrate promising results. CONCLUSIONS: The implementation of PAM-BS, included in the scellpam package, exhibits robust performance in terms of speed and memory usage compared to other related methods. PAM allowed quick and robust clustering of sets of cells with a size ranging from 70,000 to 300,000 cells. https://cran.r-project.org/web/packages/scellpam/index.html . Finally, our approach provides important new insights into the transient subpopulations associated with the fertile time frame when applied to the study of changes in the human endometrium during the secretory phase of the menstrual cycle.

A Qualitative Inquiry Exploring Clinical Faculty Transition to a Concept-Based Curriculum.

AIM: This study explores the transition process clinical faculty experience when changing to teaching in a concept-based curriculum. BACKGROUND: Literature related to faculty support during curricular change is sparse and offers little guidance to assist clinical faculty. METHOD: A qualitative study was conducted with participants from nursing programs in a statewide consortium. Semistructured interviews were transcribed to identify themes that linked participants' experiences to transition stages. Additional research included review of clinical assignments and observation of faculty while teaching at a clinical site. RESULTS: Nine clinical faculty from six nursing programs participated in the study. Five themes linked to the stages of the Bridges Transition Model were identified: Collaboration, Communication, Coordination, Coherence, and Futility. CONCLUSION: The identified themes revealed that clinical faculty varied in their transition process. These results add to the knowledge of transitional change for clinical faculty.

From nematic shells to nematic droplets: energetics and defect transitions.

In this work, we investigate the possibility of inducing valence transitions, i.e. transitions between different defect configurations, by transforming a nematic shell into a nematic droplet. Our shells are liquid crystal droplets containing a smaller aqueous droplet inside, which are suspended in an aqueous phase. When osmotically de-swelling the inner droplet, the shell progressively increases its thickness until it eventually becomes a single droplet. During the process, the shell energy landscape evolves, triggering a response in the system. We observe two different scenarios. Either the inner droplet progressively shrinks and disappears, inducing a defect reorganization, or it is expelled from the shell at a critical radius of the inner droplet, abruptly changing the geometry of the system. We use numerical simulations and modeling to investigate the origin of these behaviors. We find that the selected route depends on the defect structure and the energetics of the system as it evolves. The critical inner radius and time for expulsion depend on the osmotic pressure of the outer phase, suggesting that the flow through the shell plays a role in the process.

Temperature-Driven Anchoring Transitions at Liquid Crystal/Water Interfaces.

Controlling the anchoring of liquid crystal molecules at an interface with a water solution influences the entire organization of the underlying liquid crystal phase, which is crucial for many applications. The simplest way to stabilize such interfaces is by fabricating liquid crystal droplets in water; however, a greater sensitivity to interfacial effects can be achieved using liquid crystal shells, that is, spherical films of liquid crystal suspended in water. Anchoring transitions on those systems are traditionally triggered by the adsorption of surfactant molecules onto the interface, which is neither an instantaneous nor a reversible process. In this study, we report the ability to change the anchoring of 4-cyano-4'-pentylbiphenyl (5CB), one of the most widely used liquid crystals, at the interface with dilute water solutions of polyvinyl alcohol (PVA), a polymer commonly used for stabilizing liquid crystal shells, simply by controlling the temperature in the close vicinity of the liquid crystal clearing point. A quasi-static increase in temperature triggers an instantaneous reorientation of the molecules from parallel to perpendicular to the interfaces, owing to the local disordering effect of PVA on 5CB, prior to the phase transition of the bulk 5CB. We study this anchoring transition on both flat suspended films and spherical shells of liquid crystals. Switching anchoring entails a series of structural transformations involving the formation of transient structures in which topological defects are stabilized. The type of defect structure depends on the topology of the film. This method has the ability to influence both interfaces of the film nearly at the same time and can be applied to transform an initially polydisperse group of nematic shells into a monodisperse population of bivalent shells.

Active microfluidic transport in two-dimensional handlebodies.

Unlike traditional nematic liquid crystals, which adopt ordered equilibrium configurations compatible with the topological constraints imposed by the boundaries, active nematics are intrinsically disordered because of their self-sustained internal flows. Controlling the flow patterns of active nematics remains a limiting step towards their use as functional materials. Here we show that confining a tubulin-kinesin active nematic to a network of connected annular microfluidic channels enables controlled directional flows and autonomous transport. In single annular channels, for narrow widths, the typically chaotic streams transform into well-defined circulating flows, whose direction or handedness can be controlled by introducing asymmetric corrugations on the channel walls. The dynamics is altered when two or three annular channels are interconnected. These more complex topologies lead to scenarios of synchronization, anti-correlation, and frustration of the active flows, and to the stabilisation of high topological singularities in both the flow field and the orientational field of the material. Controlling textures and flows in these microfluidic platforms opens unexplored perspectives towards their application in biotechnology and materials science.

Structural transformations in tetravalent nematic shells induced by a magnetic field.

The role of applied fields on the structure of liquid crystals confined to shell geometries has been studied in past theoretical work, providing strategies to produce liquid crystal shells with controlled defect structure or valence. However, the predictions of such studies have not been experimentally explored yet. In this work, we study the structural transformations undergone by tetravalent nematic liquid crystal shells under a strong uniform magnetic field, using both experiments and simulations. We consider two different cases in terms of shell geometry and initial defect symmetry: (i) homogeneous shells with four s = +1/2 defects in a tetrahedral arrangement, and (ii) inhomogeneous shells with four s = +1/2 defects localized in their thinner parts. Consistently with previous theoretical results, we observe that the initial defect structure evolves into a bipolar one, in a process where the defects migrate towards the poles. Interestingly, we find that the defect trajectories and dynamics are controlled by curvature walls that connect the defects by pairs. Based on the angle between Bs, the local projection of the magnetic field on the shell surface, and n+½, a vector describing the defect orientations, we are able to predict the nature and shape of those inversion walls, and therefore, the trajectory and dynamics of the defects. This rule, based on symmetry arguments, is consistent with both experiments and simulations and applies for shells that are either homogeneous or inhomogeneous in thickness. By modifying the angle between Bs and n+½, we are able to induce, in controlled way, complex routes towards the final bipolar state. In the case of inhomogeneous shells, the specific symmetry of the shell allowed us to observe a hybrid splay-bend Helfrich wall for the first time.

Topological solitons, cholesteric fingers and singular defect lines in Janus liquid crystal shells.

Topological solitons are non-singular but topologically nontrivial structures in fields, which have fundamental significance across various areas of physics, similar to singular defects. Production and observation of singular and solitonic topological structures remain a complex undertaking in most branches of science - but in soft matter physics, they can be realized within the director field of a liquid crystal. Additionally, it has been shown that confining liquid crystals to spherical shells using microfluidics resulted in a versatile experimental platform for the dynamical study of topological transformations between director configurations. In this work, we demonstrate the triggered formation of topological solitons, cholesteric fingers, singular defect lines and related structures in liquid crystal shells. We show that to accommodate these objects, shells must possess a Janus nature, featuring both twisted and untwisted domains. We report the formation of linear and axisymmetric objects, which we identify as cholesteric fingers and skyrmions or elementary torons, respectively. We then take advantage of the sensitivity of shells to numerous external stimuli to induce dynamical transitions between various types of structures, allowing for a richer phenomenology than traditional liquid crystal cells with solid flat walls. Using gradually more refined experimental techniques, we induce the targeted transformation of cholesteric twist walls and fingers into skyrmions and elementary torons. We capture the different stages of these director transformations using numerical simulations. Finally, we uncover an experimental mechanism to nucleate arrays of axisymmetric structures on shells, thereby creating a system of potential interest for tackling crystallography studies on curved spaces.

A Novel Mutation of the NARROW LEAF 1 Gene Adversely Affects Plant Architecture in Rice (Oryza sativa L.).

Plant architecture is critical for enhancing the adaptability and productivity of crop plants. Mutants with an altered plant architecture allow researchers to elucidate the genetic network and the underlying mechanisms. In this study, we characterized a novel nal1 rice mutant with short height, small panicle, and narrow and thick deep green leaves that was identified from a cross between a rice cultivar and a weedy rice accession. Bulked segregant analysis coupled with genome re-sequencing and cosegregation analysis revealed that the overall mutant phenotype was caused by a 1395-bp deletion spanning over the last two exons including the transcriptional end site of the nal1 gene. This deletion resulted in chimeric transcripts involving nal1 and the adjacent gene, which were validated by a reference-guided assembly of transcripts followed by PCR amplification. A comparative transcriptome analysis of the mutant and the wild-type rice revealed 263 differentially expressed genes involved in cell division, cell expansion, photosynthesis, reproduction, and gibberellin (GA) and brassinosteroids (BR) signaling pathways, suggesting the important regulatory role of nal1. Our study indicated that nal1 controls plant architecture through the regulation of genes involved in the photosynthetic apparatus, cell cycle, and GA and BR signaling pathways.

Why nurses stay: Analysis of the registered nurse workforce and the relationship to work environments.

AIM: To examine how factors such as a sense of belonging to a nursing work group, work environmental characteristics, and workplace violence effects the duration of employment in professional settings in a southwest region of the United States. DESIGN: The descriptive correlational survey study conducted in 2014. METHODS: A random sample of 700 licensed registered nurses (RN) from a Board of Nursing's list of currently licensed RNs' (approximate n = 2300). Participants completed and returned four survey tools to the principal investigator. The return rate was 36.8% (258/700). RESULTS/FINDINGS: Analysis indicated that a sense of belonging, as well as supportive workplace characteristics, played a role in why nurses stay. The three survey tools provided strong correlations in the survey data and further authenticated the tools' reliability. A healthy work environment supports nurse retention. CONCLUSION: The three survey tools used in this study showed substantial and significant correlations. Although not all sub-scales correlated, those that did had strong Cronbach alpha scores. The weakest correlations were with the belongingness scale. Rapid turnover rates of nursing staff continue to plague healthcare organizations. A variety of reasons including difficult practice settings and stressful work environments contribute to the outflow of nurses. IMPACT: Health care administration and management leaders can improve retention via their efforts to continue to create and sustain healthy work environments that address affiliation, belongingness, and the characteristics that attract and retain nurses.

The great imitator with no diagnostic test: pyoderma gangrenosum.

Pyoderma gangrenosum is a rare, neutrophil-mediated, auto-inflammatory dermatosis that wound care specialists must be prepared to recognise. This condition has clinical features analogous to infectious processes. There is no specific diagnostic test and the diagnosis is usually obtained from exclusion. Its early recognition and proper management with prompt initiation of immunosuppressive therapy are essential to improve the quality of life and the prognosis of patients.

Self-Regulated Smectic Emulsion with Switchable Lasing Application.

A structurally reversible smectic liquid crystal (LC) emulsion made of semifluorinated rod-type molecules in silicon oil, which is controlled by simple heating and cooling, is presented. Without adding any kind of additives, such as surfactants, polymers or emulsifiers, and without using any special tools, such as microfluidics or gas bubbling, the LC molecules spontaneously form monodisperse spherical and myelin-like structures upon cooling from the isotropic temperature. The LC emulsion can easily trap guest materials, providing a platform for repeatable and reliable switchable emulsification. For example, this interesting system enables the realization of an on-off lasing system by confining fluorescent dyes in the LC droplets.

Threading the Spindle: A Geometric Study of Chiral Liquid Crystal Polymer Microparticles.

Polymeric particles are strong candidates for designing artificial materials capable of emulating the complex twisting-based functionality observed in biological systems. In this Letter, we provide the first detailed investigation of the swelling behavior of bipolar polymer liquid crystalline microparticles. Deswelling from the spherical bipolar configuration causes the microparticles to contract anisotropically and twist in the process, resulting in a twisted spindle-shaped structure. We propose a model to describe the observed spiral patterns and twisting behavior.

Waltzing route toward double-helix formation in cholesteric shells.

Liquid crystals, when confined to a spherical shell, offer fascinating possibilities for producing artificial mesoscopic atoms, which could then self-assemble into materials structured at a nanoscale, such as photonic crystals or metamaterials. The spherical curvature of the shell imposes topological constraints in the molecular ordering of the liquid crystal, resulting in the formation of defects. Controlling the number of defects, that is, the shell valency, and their positions, is a key success factor for the realization of those materials. Liquid crystals with helical cholesteric order offer a promising, yet unexplored way of controlling the shell defect configuration. In this paper, we study cholesteric shells with monovalent and bivalent defect configurations. By bringing together experiments and numerical simulations, we show that the defects appearing in these two configurations have a complex inner structure, as recently reported for simulated droplets. Bivalent shells possess two highly structured defects, which are composed of a number of smaller defect rings that pile up through the shell. Monovalent shells have a single radial defect, which is composed of two nonsingular defect lines that wind around each other in a double-helix structure. The stability of the bivalent configuration against the monovalent one is controlled by c = h/p, where h is the shell thickness and p the cholesteric helical pitch. By playing with the shell geometry, we can trigger the transition between the two configurations. This transition involves a fascinating waltz dynamics, where the two defects come closer while turning around each other.

Topological defects in cholesteric liquid crystal shells.

We investigate experimentally and numerically the defect configurations emerging when a cholesteric liquid crystal is confined to a spherical shell. We uncover a rich scenario of defect configurations, some of them non-existent in nematic shells, where new types of defects are stabilized by the helical ordering of the liquid crystal. In contrast to nematic shells, here defects are not simple singular points or lines, but have a large structured core. Specifically, we observe five different types of cholesteric shells. We study the statistical distribution of the different types of shells as a function of the two relevant geometrical dimensionless parameters of the system. By playing with these parameters, we are able to induce transitions between different types of shells. These transitions involve interesting topological transformations in which the defects recombine to form new structures. Surprisingly, the defects do not approach each other by taking the shorter distance route (geodesic), but by following intricate paths.

Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial.

It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high-resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean ± standard error of the mean: -1.3% ± 1.4% vs. -3.1% ± 2.3%, respectively), cerebrum (-1.3% ± 1.5% vs. -3.2% ± 2.1%, respectively), parietal lobe (-1.6% ± 1.9% vs. -4.1% ± 3.0%, respectively), and occipital lobe (-0.3% ± 1.8% vs. -2.7% ± 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes.

A phase 2 trial of the GSK-3 inhibitor tideglusib in progressive supranuclear palsy.

It is believed that glycogen synthase kinase-3 (GSK-3) hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) study was a double-blind, placebo-controlled, randomized trial to assess the efficacy, safety, and tolerability of tideglusib, a GSK-3 inhibitor, as potential treatment for PSP. The study enrolled 146 PSP patients with mild-to-moderate disease who were randomized to receive once-daily 600 mg tideglusib, 800 mg tideglusib, or placebo (ratio, 2:2:1) administered orally over 52 weeks. The primary endpoint was the change from baseline to week 52 on the PSP rating scale. Secondary endpoints were safety and tolerability of tideglusib, changes in motor function (the Timed Up and Go Test), cognition (Dementia Rating Scale-2, Frontal Assessment Battery, verbal fluency), apathy (Starkstein scale), activities of daily living (Schwab and England scale; Unified Parkinson's Disease Rating Scale, part II), quality of life (EuroQol), and Global Clinical Assessment. Brain atrophy on magnetic resonance imaging and several biomarkers in plasma and cerebrospinal fluid also were examined. No significant differences were detected in the primary or secondary endpoints at week 52 between placebo and either dose of tideglusib. Tideglusib was safe, with the exception of some asymptomatic, transient, and reversible transaminase elevations (mainly alanine aminotransferase) in 9% of patients, and diarrhea in 13% of patients. Tideglusib was generally well tolerated but it did not show clinical efficacy in patients with mild-to-moderate PSP.

Progression analysis versus traditional methods to quantify slowing of disease progression in Alzheimer's disease.

BACKGROUND: The clinical meaningfulness of the effects of recently approved disease-modifying treatments (DMT) in Alzheimer's disease is under debate. Available evidence is limited to short-term effects on clinical rating scales which may be difficult to interpret and have limited intrinsic meaning to patients. The main value of DMTs accrues over the long term as they are expected to cause a delay or slowing of disease progression. While awaiting such evidence, the translation of short-term effects to time delays or slowing of progression could offer a powerful and readily interpretable representation of clinical outcomes. METHODS: We simulated disease progression trajectories representing two arms, active and placebo, of a hypothetical clinical trial of a DMT. The placebo arm was simulated based on estimated mean trajectories of clinical dementia rating scale-sum of boxes (CDR-SB) recordings from amyloid-positive subjects with mild cognitive impairment (MCI) from Alzheimer's Disease Neuroimaging Initiative (ADNI). The active arm was simulated to show an average slowing of disease progression versus placebo of 20% at each visit. The treatment effects in the simulated trials were estimated with a progression model for repeated measures (PMRM) and a mixed model for repeated measures (MMRM) for comparison. For PMRM, the treatment effect is expressed in units of time (e.g., days) and for MMRM in units of the outcome (e.g., CDR-SB points). PMRM results were implemented in a health economics Markov model extrapolating disease progression and death over 15 years. RESULTS: The PMRM model estimated a 19% delay in disease progression at 18 months and 20% (~ 7 months delay) at 36 months, while the MMRM model estimated a 25% reduction in CDR-SB (~ 0.5 points) at 36 months. The PMRM model had slightly greater power compared to MMRM. The health economic model based on the estimated time delay suggested an increase in life expectancy (10 months) without extending time in severe stages of disease. CONCLUSION: PMRM methods can be used to estimate treatment effects in terms of slowing of progression which translates to time metrics that can be readily interpreted and appreciated as meaningful outcomes for patients, care partners, and health care practitioners.

Interactions between proteins and cellulose in a liquid crystalline media: Design of a droplet based experimental platform.

Model systems are needed to provide controlled environment for the understanding of complex phenomena. Interaction between polysaccharides and proteins in dense medium are involved in numerous complex systems such as biomass conversion or plant use for food processing or biobased materials. In this work, cellulose nanocrystals (CNCs) were used to study proteins in a dense and organized cellulosic environment. This environment was designed within microdroplets using a microfluidic setup, and applied to two proteins, bovine serum albumin (BSA) and a GH7 endoglucanase, relevant to food and plant science, respectively. The CNC at 56.5 g/L organized in liquid crystalline structure and the distribution of the proteins was probed using synchrotron deep-UV radiation. The proteins were homogeneously distributed throughout the volume, but BSA significantly disturbed the droplet global organization, preferring partition in hydrophilic external micelles. In contrast, GH7 partitioned with the CNCs showing stronger non-polar interaction but without disruption of the system organization. Such results pave the road for the development of more complex polysaccharides - proteins in-vitro models.