Summary: dendextend is an R package for creating and comparing visually appealing tree diagrams. dendextend provides utility functions for manipulating dendrogram objects (their color, shape and content) as well as several advanced methods for comparing trees to one another (both statistically and visually). As such, dendextend offers a flexible framework for enhancing R's rich ecosystem of packages for performing hierarchical clustering of items.Availability and implementation: The dendextend R package (including detailed introductory vignettes) is available under the GPL-2 Open Source license and is freely available to download from CRAN at: (http://cran.r-project.org/package=dendextend)Contact: Tal.Galili@math.tau.ac.il

Summary heatmaply is an R package for easily creating interactive cluster heatmaps that can be shared online as a stand-alone HTML file. Interactivity includes a tooltip display of values when hovering over cells, as well as the ability to zoom in to specific sections of the figure from the data matrix, the side dendrograms, or annotated labels. Thanks to the synergistic relationship between heatmaply and other R packages, the user is empowered by a refined control over the statistical and visual aspects of the heatmap layout.Availability and implementationThe heatmaply package is available under the GPL-2 Open Source license. It comes with a detailed vignette, and is freely available from: http://cran.r-project.org/package=heatmaply.Supplementary information Supplementary data are available at Bioinformatics online.

Maintaining posture requires tight regulation of the position and orientation of numerous spinal components. Yet, surprisingly little is known about this regulatory mechanism, whose failure may result in spinal deformity as in adolescent idiopathic scoliosis. Here, we use genetic mouse models to demonstrate the involvement of proprioception in regulating spine alignment. Null mutants for Runx3 transcription factor, which lack TrkC neurons connecting between proprioceptive mechanoreceptors and spinal cord, developed peripubertal scoliosis not preceded by vertebral dysplasia or muscle asymmetry. Deletion of Runx3 in the peripheral nervous system or specifically in peripheral sensory neurons, or of enhancer elements driving Runx3 expression in proprioceptive neurons, induced a similar phenotype. Egr3 knockout mice, lacking muscle spindles, but not Golgi tendon organs, displayed a less severe phenotype, suggesting that both receptor types may be required for this regulatory mechanism. These findings uncover a central role for the proprioceptive system in maintaining spinal alignment.

To obtain a perspective on an animal's own functional world, we study its behavior in situations that allow the animal to regulate the growth rate of its behavior and provide us with the opportunity to quantify its moment-by-moment developmental dynamics. Thus, we are able to show that mouse exploratory behavior consists of sequences of repeated motion: iterative processes that increase in extent and complexity, whose presumed function is a systematic active management of input acquired during the exploration of a novel environment. We use this study to demonstrate our approach to quantifying behavior: targeting aspects of behavior that are shown to be actively managed by the animal, and using measures that are discriminative across strains and treatments and replicable across laboratories.

Background and aimsAlthough smoking cessation medications have shown effectiveness in increasing abstinence in randomized controlled trials (RCTs), it is unclear to what extent benefits persist over time. This paper assesses whether the benefits of smoking cessation medications decline over the first year.MethodsWe selected studies from three systematic reviews published by the Cochrane Collaboration. RCTs of first‐line smoking cessation medications, with 6‐ and 12‐month follow‐up, were eligible for inclusion. Meta‐analysis was used to synthesize information on sustained abstinence (SA) at 6 versus 12 months and 3 versus 6 months, using the risk difference (RD) (‘net benefit’) between intervention and control group quit rates, the relative risk (RR) and the odds ratio (OR).ResultsSixty‐one studies (27 647 participants) were included. Fewer than 40% of intervention group participants were sustained abstinent at 3 months (bupropion: 37.1%; nicotine replacement therapy (NRT): 34.8%; varenicline: 39.3%); approximately a quarter were sustained abstinent at 6 months (bupropion: 25.9%; NRT: 26.6%; varenicline: 25.4%), and approximately a fifth were sustained abstinent at 12 months (bupropion: 19.9%; NRT: 19.8%%; varenicline: 18.7%). There was only a small decline in RR (3 months: 1.95 [95% confidence interval (CI) = 1.74–2.18, P < 0.0001]; 6 months: 1.87 (95% CI = 1.67–2.08 P < 0.0001); 12 months: 1.75 (95% CI = 1.56–1.95, P < 0.0001) between intervention and control groups over time, but a substantial decline in net benefit [3 months: RD = 17.3% (14.5–20.1%); 6 months: RD = 11.8% (10.0–13.7%); 12 months: RD = 8.2% (6.8–9.6%)]. The decline in net benefit was statistically significant between 3 and 6 [RD = 4.95% (95% CI = 3.49–6.41%), P < 0.0001] and 6 and 12 months [RD = 3.00% (95% CI = 2.36%–3.64%), P < 0.0001)] for medications combined and individual medications.ConclusionsThe proportion of smokers who use smoking cessation medications who benefit from doing so decreases during the course of the first year, but a net benefit still remains at 12 months.

The population of adults with Alzheimer's disease (AD) varies in needs and outcomes. The heterogeneity of current AD diagnostic subgroups impedes the use of data analytics in clinical trial design and translation of findings into improved care. The purpose of this project was to define more clinicallyhomogeneous groups of AD patients and link clinical characteristics with biological markers. We used an innovative big data analysis strategy, the 3C strategy, that incorporates medical knowledge into the data analysis process. A large set of preprocessed AD Neuroimaging Initiative (ADNI) data was analyzed with 3C. The data analysis yielded 6 new disease subtypes, which differ from the assigned diagnosis types and present different patterns of clinical measures and potential biomarkers. Two of the subtypes, "Anosognosia dementia" and "Insightful dementia", differentiate between severe participants based on clinical characteristics and biomarkers. The "Uncompensated mild cognitive impairment (MCI)" subtype, demonstrates clinical, demographic and imaging differences from the "Affective MCI" subtype. Differences were also observed between the "Worried Well" and "Healthy" clusters. The use of data-driven analysis yielded sub-phenotypic clinical clusters that go beyond current diagnoses and are associated with biomarkers. Such homogenous subgroups can potentially form the basis for enhancement of brain medicine research. Alzheimer's disease (AD) is a degenerative brain disease and the most common cause of dementia 1 according to the 2018 Alzheimer's association report 2 an estimated 5.7 million Americans of all ages are living with AD in 2018. The percentage of people with AD increases with age: 3% of people age 65-74, 17% of people age 75-84, and 32% of people age 85 and older have AD 3. Symptoms vary among people with AD, and the differences between typical age-related cognitive changes and early signs of AD can be subtle. The definite diagnosis of AD, requiring histopathological examination, is characterized by the accumulation of β-amyloid (Aβ) plaques and neurofibrillary tangles composed of tau amyloid fibrils associated with brain cell damage and neurodegeneration 4. In clinical practice, the diagnosis of AD is based on clinical criteria, while laboratory and imaging examinations are used to exclude other diagnoses. Sub classification of AD has been previously attempted, mostly based on a small set of parameters or on a single modality 5,6 , and in some studies has relied only on previous knowledge. Current diagnostic subgroupings are informative, however, they are quite crude as they are based on rough criteria 7,8. This may lead astray supervised data mining tools that rely solely on these definitions while trying to predict or associate disease manifestation with clinical and biological markers. Thus, for the search of new insights, it is essential to use unsupervised processes, which do not rely on the current diagnostic subgroupings, Nevertheless, despite numerous attempts to use unsupervised processes as progn...

One of the major challenges that developing organs face is scaling, that is, the adjustment of physical proportions during the massive increase in size. Although organ scaling is fundamental for development and function, little is known about the mechanisms that regulate it. Bone superstructures are projections that typically serve for tendon and ligament insertion or articulation and, therefore, their position along the bone is crucial for musculoskeletal functionality. As bones are rigid structures that elongate only from their ends, it is unclear how superstructure positions are regulated during growth to end up in the right locations. Here, we document the process of longitudinal scaling in developing mouse long bones and uncover the mechanism that regulates it. To that end, we performed a computational analysis of hundreds of three-dimensional micro-CT images, using a newly developed method for recovering the morphogenetic sequence of developing bones. Strikingly, analysis revealed that the relative position of all superstructures along the bone is highly preserved during more than a 5-fold increase in length, indicating isometric scaling. It has been suggested that during development, bone superstructures are continuously reconstructed and relocated along the shaft, a process known as drift. Surprisingly, our results showed that most superstructures did not drift at all. Instead, we identified a novel mechanism for bone scaling, whereby each bone exhibits a specific and unique balance between proximal and distal growth rates, which accurately maintains the relative position of its superstructures. Moreover, we show mathematically that this mechanism minimizes the cumulative drift of all superstructures, thereby optimizing the scaling process. Our study reveals a general mechanism for the scaling of developing bones. More broadly, these findings suggest an evolutionary mechanism that facilitates variability in bone morphology by controlling the activity of individual epiphyseal plates.

SummarySuccessful fracture repair requires restoration of bone morphology and mechanical integrity. Recent evidence shows that fractured bones of neonatal mice undergo spontaneous realignment, dubbed “natural reduction.” Here, we show that natural reduction is regulated by the proprioceptive system and improves with age. Comparison among mice of different ages revealed, surprisingly, that 3-month-old mice exhibited more rapid and effective natural reduction than newborns. Fractured bones of null mutants for transcription factor Runx3, lacking functional proprioceptors, failed to realign properly. Blocking Runx3 expression in the peripheral nervous system, but not in limb mesenchyme, recapitulated the null phenotype, as did inactivation of muscles flanking the fracture site. Egr3 knockout mice, which lack muscle spindles but not Golgi tendon organs, displayed a less severe phenotype, suggesting that both receptor types, as well as muscle contraction, are required for this regulatory mechanism. These findings uncover a physiological role for proprioception in non-autonomous regulation of skeletal integrity.