Heterotopic ossification is a debilitating condition that can result from traumatic injury, surgery, or genetic disease. We investigated the cellular origins of heterotopic skeletogenesis in the mouse using lineage tracing and bioassays of heterotopic ossification based on intramuscular transplantation. We identify, characterize and purify a tissue-resident stem/progenitor cell population that exhibits robust osteogenic potential and represents a major cell-of-origin for heterotopic ossification. These progenitors reside in the interstitium of skeletal muscle and other tissues, and are distinct from the endothelium, which does not exhibit osteogenic activity in response to BMP2 stimulation. Intramuscular transplantation together with clonal analysis in culture revealed that these progenitors are multipotent, exhibiting the capacity for both BMP-dependent skeletogenic differentiation and spontaneous adipogenic differentiation. Identifying the cells-of-origin responsible for heterotopic ossification provides a potential therapeutic target to treat, mitigate or prevent this disabling condition.

Fibrodysplasia ossificans progressiva (FOP) is a rare autosomal-dominant disorder characterized by progressive and profoundly disabling heterotopic ossification (HO). Here we show that fibro/adipogenic progenitors (FAPs) are a major cell-of-origin of HO in an accurate genetic mouse model of FOP (Acvr1tnR206H). Targeted expression of the disease-causing type I bone morphogenetic protein (BMP) receptor, ACVR1(R206H), to FAPs recapitulates the full spectrum of HO observed in FOP patients. ACVR1(R206H)-expressing FAPs, but not wild-type FAPs, activate osteogenic signaling in response to activin ligands. Conditional loss of the wild-type Acvr1 allele dramatically exacerbates FAP-directed HO, suggesting that mutant and wild-type ACVR1 receptor complexes compete for activin ligands or type II BMP receptor binding partners. Finally, systemic inhibition of activin A completely blocks HO and restores wild-type-like behavior to transplanted Acvr1R206H/+ FAPs. Understanding the cells that drive HO may facilitate the development of cell-specific therapeutic approaches to inhibit catastrophic bone formation in FOP.

We investigate the problem of fair recommendation in the context of two-sided online platforms, comprising customers on one side and producers on the other. Traditionally, recommendation services in these platforms have focused on maximizing customer satisfaction by tailoring the results according to the personalized preferences of individual customers. However, our investigation reveals that such customer-centric design may lead to unfair distribution of exposure among the producers, which may adversely impact their well-being. On the other hand, a producer-centric design might become unfair to the customers. Thus, we consider fairness issues that span both customers and producers. Our approach involves a novel mapping of the fair recommendation problem to a constrained version of the problem of fairly allocating indivisible goods. Our proposed FairRec algorithm guarantees at least Maximin Share (MMS) of exposure for most of the producers and Envy-Free up to One item (EF1) fairness for every customer. Extensive evaluations over multiple real-world datasets show the effectiveness of FairRec in ensuring two-sided fairness while incurring a marginal loss in the overall recommendation quality. CCS CONCEPTS• Information systems → Recommender systems.

We consider the problem of fairly allocating indivisible goods, among agents, under cardinality constraints and additive valuations. In this setting, we are given a partition of the entire set of goods---i.e., the goods are categorized---and a limit is specified on the number of goods that can be allocated from each category to any agent. The objective here is to find a fair allocation in which the subset of goods assigned to any agent satisfies the given cardinality constraints. This problem naturally captures a number of resource-allocation applications, and is a generalization of the well-studied unconstrained fair division problem.  The two central notions of fairness, in the context of fair division of indivisible goods, are envy freeness up to one good (EF1) and the (approximate) maximin share guarantee (MMS). We show that the existence and algorithmic guarantees established for these solution concepts in the unconstrained setting can essentially be achieved under cardinality constraints. Furthermore, focusing on the case wherein all the agents have the same additive valuation, we establish that EF1 allocations exist even under matroid constraints.

SummaryMyoD and Myf5 are fundamental regulators of skeletal muscle lineage determination in the embryo, and their expression is induced in satellite cells following muscle injury. MyoD and Myf5 are also expressed by satellite cell precursors developmentally, although the relative contribution of historical and injury-induced expression to satellite cell function is unknown. We show that satellite cells lacking both MyoD and Myf5 (double knockout [dKO]) are maintained with aging in uninjured muscle. However, injured muscle fails to regenerate and dKO satellite cell progeny accumulate in damaged muscle but do not undergo muscle differentiation. dKO satellite cell progeny continue to express markers of myoblast identity, although their myogenic programming is labile, as demonstrated by dramatic morphological changes and increased propensity for non-myogenic differentiation. These data demonstrate an absolute requirement for either MyoD or Myf5 in muscle regeneration and indicate that their expression after injury stabilizes myogenic identity and confers the capacity for muscle differentiation.