The Fixed Landscape Inference MethOd (flimo): a versatile alternative to Approximate Bayesian Computation, faster by several orders of magnitude

Modelling in biology must adapt to increasingly complex and massive data. The efficiency of the inference algorithms used to estimate model parameters is therefore questioned. Many of these are based on stochastic optimization processes that require significant computing time. We introduce the Fixed Landscape Inference MethOd (flimo), a new likelihood-free inference method for continuous state-space stochastic models. It applies deterministic gradient-based optimization algorithms to obtain a point estimate of the parameters, minimizing the difference between the data and some simulations according to some prescribed summary statistics. In this sense, it is analogous to Approximate Bayesian Computation (ABC). Like ABC, it can also provide an approximation of the distribution of the parameters. Three applications are proposed: a usual theoretical example, namely the inference of the parameters of g-and-k distributions; a population genetics problem, not so simple as it seems, namely the inference of a selective value from time series in a Wright-Fisher model; and simulations from a Ricker model, representing chaotic population dynamics. In the two first applications, the results show a drastic reduction of the computational time needed for the inference phase compared to the other methods, despite an equivalent accuracy. Even when likelihood-based methods are applicable, the simplicity and efficiency of flimo make it a compelling alternative. Implementations in Julia and in R are available on https://metabarcoding.org/flimo. To run flimo, the user must simply be able to simulate data according to the chosen model

Management of massive rotator cuff tears: prospective study in 218 patients

BACKGROUND: No consensus exists about the management of massive and symptomatic rotator cuff tears (RCTs). The objective of this study was to compare the 12-month clinical outcomes of various treatment options for massive RCTs. HYPOTHESIS: Arthroscopic surgery has a role to play in the treatment of massive and apparently irreparable RCTs. MATERIAL AND METHODS: A prospective multicentre non-randomised study was performed in patients with massive RCTs managed non-operatively (NONOP) or by arthroscopic tenotomy/tenodesis of the long head of biceps (aTLB), arthroscopic partial tendon repair (aPTR), arthroscopic latissimus dorsi transfer (aLDT), or reverse shoulder arthroplasty (RSA). Clinical outcomes were evaluated based on the Constant score, Subjective Shoulder Value (SSV), and American Shoulder and Elbow Surgeons (ASES) score after 3, 6, and 12 months. RESULTS: The 218 included patients (mean age, 69 years) were distributed as follows: NONOP, n=71; aTLB, n=26; aPTR, n=61; aLDT, n=25; and RSA, n=35. After 12 months, the mean Constant score, SSV, and ASES score values were 70, 68%, and 73, respectively, and had improved significantly versus the preoperative values in all treatment groups. RSA was the only treatment followed by improvements in all Constant score items. Active forwards elevation improved significantly in the NONOP (+25°), aPTR (+26°), and RSA (+66°) groups. An improvement in active external rotation was seen only in the RSA group, where it was small (+10°, p=0.046). Significant increases in internal rotation were seen in the NONOP (+1.6 points) and aPTR (+1.7 points) groups. CONCLUSION: Arthroscopic techniques (aTLB, aPTR, and aLDT) for managing massive irreparable RCTs produce significant functional gains. Partial tendon repair (aPTR) and RSA may provide better outcomes than isolated aTLB or aLDT

In Vivo Chromatin Organization of Mouse Rod Photoreceptors Correlates with Histone Modifications

BACKGROUND: The folding of genetic information into chromatin plays important regulatory roles in many nuclear processes and particularly in gene transcription. Post translational histone modifications are associated with specific chromatin condensation states and with distinct transcriptional activities. The peculiar chromatin organization of rod photoreceptor nuclei, with a large central domain of condensed chromatin surrounded by a thin border of extended chromatin was used as a model to correlate in vivo chromatin structure, histone modifications and transcriptional activity. METHODOLOGY: We investigated the functional relationships between chromatin compaction, distribution of histone modifications and location of RNA polymerase II in intact murine rod photoreceptors using cryo-preparation methods, electron tomography and immunogold labeling. Our results show that the characteristic central heterochromatin of rod nuclei is organized into concentric domains characterized by a progressive loosening of the chromatin architecture from inside towards outside and by specific combinations of silencing histone marks. The peripheral heterochromatin is formed by closely packed 30 nm fibers as revealed by a characteristic optical diffraction signal. Unexpectedly, the still highly condensed most external heterochromatin domain contains acetylated histones, which are usually associated with active transcription and decondensed chromatin. Histone acetylation is thus not sufficient in vivo for complete chromatin decondensation. The euchromatin domain contains several degrees of chromatin compaction and the histone tails are hyperacetylated, enriched in H3K4 monomethylation and hypo trimethylated on H3K9, H3K27 and H4K20. The transcriptionally active RNA polymerases II molecules are confined in the euchromatin domain and are preferentially located at the vicinity of the interface with heterochromatin. CONCLUSIONS: Our results show that transcription is located in the most decondensed and highly acetylated chromatin regions, but since acetylation is found associated with compact chromatin it is not sufficient to decondense chromatin in vivo. We also show that a combination of histone marks defines distinct concentric heterochromatin domains

Approche hydrodynamique des mouvements de cellules en interaction avec la paroi endothéliale, grâce à des Méthodes Level Set

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