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Intraamniotic administration of a recombinant portion of ectodysplasin A to three fetuses with X-linked hypohydrotic ectodermal dysplasia (caused by mutations in the gene encoding ectodysplasin A) was followed by the birth of healthy infants who could sweat normally.

Thermal acclimation of photosynthesis, the physiological adjustment to temperature over weeks, may help plants mitigate adverse impacts of global warming, but is often under‐represented in Earth System Models (ESMs). We evaluated a plant functional type (PFT)‐agnostic, optimality‐based model of C3 ${\\mathrm{C}}_{3}$ photosynthesis with a global data set of leaf gas exchange measurements. We investigated how three key photosynthesis traits vary along a gradient of growing‐season temperatures Tgrowth $\\left({T}_{\\text{growth}}\\right)$: optimal photosynthesis temperature Topt $\\left({T}_{\\text{opt}}\\right)$, net photosynthesis rate at Topt ${T}_{\\text{opt}}$ Aopt $\\left({A}_{\\text{opt}}\\right)$, and the width of the temperature response curve Tspan $\\left({T}_{\\text{span}}\\right)$. We analyzed how each trait is influenced by three acclimation processes: acclimation of photosynthetic capacities (carboxylation, electron transport, and respiration), their enzymatic responses, and stomatal sensitivity to vapor pressure deficit. The inclusion of all three acclimation processes was essential for reproducing observed patterns: a linear increase in Topt ${T}_{\\text{opt}}$ with Tgrowth ${T}_{\\text{growth}}$, and no correlations of Aopt ${A}_{\\text{opt}}$ and Tspan ${T}_{\\text{span}}$ with Tgrowth ${T}_{\\text{growth}}$. Acclimation of enzymatic responses and stomatal sensitivity was crucial for accurately predicting Topt ${T}_{\\text{opt}}$ and Tspan ${T}_{\\text{span}}$. Acclimation of the photosynthetic capacities was necessary to avoid a bias in Aopt ${A}_{\\text{opt}}$ that can arise when relying on static, PFT‐specific parameters. Comparing a model with all and a model without any acclimation processes showed that thermal acclimation buffers the response of photosynthesis to warming substantially, leading to smaller increases in photosynthesis in cold climates (+2% instead of +18%) and smaller declines in warm climates (−4% instead of −22%). Our observations‐constrained photosynthesis predictions suggest an important role of thermal acclimation in ESM, partly mitigating adverse effects of a warming climate. Plain Language Summary Plants adjust their photosynthetic apparatus in response to gradual temperature changes over weeks, a mechanism known as thermal acclimation. This acclimation may help plants mitigate the impacts of global warming, but many models that predict the response of vegetation to a changing climate often under‐represent it. In this study, we tested a photosynthesis model that predicts a plant's response to gradual temperature changes based on general principles rather than specific plant types. These principles, stemming from optimality theory and fundamental biochemistry, describe thermal acclimation through different internal processes that regulate the use of carbon, water, and energy. We compared the model with a global data set of leaf measurements to disentangle the influence of these processes on photosynthesis. We found that to accurately predict observed patterns, it was essential to include three acclimation processes: adjustments in photosynthetic capacities, enzyme activities, and stomatal response. The model showed that thermal acclimation buffers plants against the effect of global warming, leading to smaller increases in photosynthesis in cold climates and smaller declines in warm climates compared to models without acclimation. This study highlights the importance of incorporating thermal acclimation into vegetation models to improve predictions of plant responses under future climate scenarios. Key Points Thermal acclimation of C3 ${\\mathrm{C}}_{3}$ photosynthesis is predictable across species and climates using optimality theory and fundamental biochemistry Combined acclimation of photosynthetic capacities, enzyme activity, and stomatal response was critical to capture observations Thermal acclimation buffers photosynthesis against warming, reducing increases in cold climates and limiting declines in hot climates

The mouse mammary gland develops postnatally under the control of female reproductive hormones. Estrogens and progesterone trigger morphogenesis by poorly understood mechanisms acting on a subset of mammary epithelial cells (MECs) that express their cognate receptors, estrogen receptor α (ERα) and progesterone receptor (PR). Here, we show that in the adult female, progesterone drives proliferation of MECs in two waves. The first, small wave, encompasses PR(+) cells and requires cyclin D1, the second, large wave, comprises mostly PR(-) cells and relies on the tumor necrosis factor (TNF) family member, receptor activator of NF-κB-ligand (RANKL). RANKL elicits proliferation by a paracrine mechanism. Ablation of RANKL in the mammary epithelium blocks progesterone-induced morphogenesis, and ectopic expression of RANKL in MECs completely rescues the PR⁻/⁻ phenotype. Systemic administration of RANKL triggers proliferation in the absence of PR signaling, and injection of a RANK signaling inhibitor interferes with progesterone-induced proliferation. Thus, progesterone elicits proliferation by a cell-intrinsic and a, more important, paracrine mechanism.

Antibody-secreting plasma cells (PCs) arise rapidly during adaptive immunity to control infections. The early PCs are retained within the reactive lymphoid organ where their localization and homeostasis rely on extrinsic factors, presumably produced by local niche cells. While myeloid cells have been proposed to form those niches, the contribution by colocalizing stromal cells has remained unclear. Here, we characterized a subset of fibroblastic reticular cells (FRCs) that forms a dense meshwork throughout medullary cords of lymph nodes (LNs) where PCs reside. This medullary FRC type is shown to be anatomically, phenotypically, and functionally distinct from T zone FRCs, both in mice and humans. By using static and dynamic imaging approaches, we provide evidence that medullary FRCs are the main cell type in contact with PCs guiding them in their migration. Medullary FRCs also represent a major local source of the PC survival factors IL-6, BAFF, and CXCL12, besides also producing APRIL. In vitro, medullary FRCs alone or in combination with macrophages promote PC survival while other LN cell types do not have this property. Thus, we propose that this FRC subset, together with medullary macrophages, forms PC survival niches within the LN medulla, and thereby helps in promoting the rapid development of humoral immunity, which is critical in limiting early pathogen spread.

When patterns are set during embryogenesis, it is expected that they are straightly established rather than subsequently modified. The patterning of the three mouse molars is, however, far from straight, likely as a result of mouse evolutionary history. The first-formed tooth signaling centers, called MS and R2, disappear before driving tooth formation and are thought to be vestiges of the premolars found in mouse ancestors. Moreover, the mature signaling center of the first molar (M1) is formed from the fusion of two signaling centers (R2 and early M1). Here, we report that broad activation of Edar expression precedes its spatial restriction to tooth signaling centers. This reveals a hidden two-step patterning process for tooth signaling centers, which was modeled with a single activator-inhibitor pair subject to reaction-diffusion (RD). The study of Edar expression also unveiled successive phases of signaling center formation, erasing, recovering, and fusion. Our model, in which R2 signaling center is not intrinsically defective but erased by the broad activation preceding M1 signaling center formation, predicted the surprising rescue of R2 in Edar mutant mice, where activation is reduced. The importance of this R2-M1 interaction was confirmed by ex vivo cultures showing that R2 is capable of forming a tooth. Finally, by introducing chemotaxis as a secondary process to RD, we recapitulated in silico different conditions in which R2 and M1 centers fuse or not. In conclusion, pattern formation in the mouse molar field relies on basic mechanisms whose dynamics produce embryonic patterns that are plastic objects rather than fixed end points.

Atherosclerotic cardiovascular disease causes heart attacks and strokes, which are the leading causes of mortality worldwide 1 . The formation of atherosclerotic plaques is initiated when low-density lipoproteins bind to heparan-sulfate proteoglycans (HSPGs) 2 and become trapped in the subendothelial space of large and medium size arteries, which leads to chronic inflammation and remodelling of the artery wall 2 . A proliferation-inducing ligand (APRIL) is a cytokine that binds to HSPGs 3 , but the physiology of this interaction is largely unknown. Here we show that genetic ablation or antibody-mediated depletion of APRIL aggravates atherosclerosis in mice. Mechanistically, we demonstrate that APRIL confers atheroprotection by binding to heparan sulfate chains of heparan-sulfate proteoglycan 2 (HSPG2), which limits the retention of low-density lipoproteins, accumulation of macrophages and formation of necrotic cores. Indeed, antibody-mediated depletion of APRIL in mice expressing heparan sulfate-deficient HSPG2 had no effect on the development of atherosclerosis. Treatment with a specific anti-APRIL antibody that promotes the binding of APRIL to HSPGs reduced experimental atherosclerosis. Furthermore, the serum levels of a form of human APRIL protein that binds to HSPGs, which we termed non-canonical APRIL (nc-APRIL), are associated independently of traditional risk factors with long-term cardiovascular mortality in patients with atherosclerosis. Our data reveal properties of APRIL that have broad pathophysiological implications for vascular homeostasis. The heparan sulfate proteoglycan-binding cytokine APRIL has a protective role against atherosclerotic disease.

Feathers are arranged in a precise pattern in avian skin. They first arise during development in a row along the dorsal midline, with rows of new feather buds added sequentially in a spreading wave. We show that the patterning of feathers relies on coupled fibroblast growth factor (FGF) and bone morphogenetic protein (BMP) signalling together with mesenchymal cell movement, acting in a coordinated reaction-diffusion-taxis system. This periodic patterning system is partly mechanochemical, with mechanical-chemical integration occurring through a positive feedback loop centred on FGF20, which induces cell aggregation, mechanically compressing the epidermis to rapidly intensify FGF20 expression. The travelling wave of feather formation is imposed by expanding expression of Ectodysplasin A (EDA), which initiates the expression of FGF20. The EDA wave spreads across a mesenchymal cell density gradient, triggering pattern formation by lowering the threshold of mesenchymal cells required to begin to form a feather bud. These waves, and the precise arrangement of feather primordia, are lost in the flightless emu and ostrich, though via different developmental routes. The ostrich retains the tract arrangement characteristic of birds in general but lays down feather primordia without a wave, akin to the process of hair follicle formation in mammalian embryos. The embryonic emu skin lacks sufficient cells to enact feather formation, causing failure of tract formation, and instead the entire skin gains feather primordia through a later process. This work shows that a reaction-diffusion-taxis system, integrated with mechanical processes, generates the feather array. In flighted birds, the key role of the EDA/Ectodysplasin A receptor (EDAR) pathway in vertebrate skin patterning has been recast to activate this process in a quasi-1-dimensional manner, imposing highly ordered pattern formation.

We present TIMo (Time-of-flight Indoor Monitoring), a dataset for video-based monitoring of indoor spaces captured using a time-of-flight (ToF) camera. The resulting depth videos feature people performing a set of different predefined actions, for which we provide detailed annotations. Person detection for people counting and anomaly detection are the two targeted applications. Most existing surveillance video datasets provide either grayscale or RGB videos. Depth information, on the other hand, is still a rarity in this class of datasets in spite of being popular and much more common in other research fields within computer vision. Our dataset addresses this gap in the landscape of surveillance video datasets. The recordings took place at two different locations with the ToF camera set up either in a top-down or a tilted perspective on the scene. Moreover, we provide experimental evaluation results from baseline algorithms.

BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.

APO2L/TRAIL (TNF-related apoptosis-inducing ligand) induces death of tumor cells through two agonist receptors, TRAIL-R1 and TRAIL-R2. We demonstrate here that N-linked glycosylation ( N -glyc) plays also an important regulatory role for TRAIL-R1-mediated and mouse TRAIL receptor (mTRAIL-R)-mediated apoptosis, but not for TRAIL-R2, which is devoid of N -glycans. Cells expressing N -glyc-defective mutants of TRAIL-R1 and mouse TRAIL-R were less sensitive to TRAIL than their wild-type counterparts. Defective apoptotic signaling by N -glyc-deficient TRAIL receptors was associated with lower TRAIL receptor aggregation and reduced DISC formation, but not with reduced TRAIL-binding affinity. Our results also indicate that TRAIL receptor N -glyc impacts immune evasion strategies. The cytomegalovirus (CMV) UL141 protein, which restricts cell-surface expression of human TRAIL death receptors, binds with significant higher affinity TRAIL-R1 lacking N -glyc, suggesting that this sugar modification may have evolved as a counterstrategy to prevent receptor inhibition by UL141. Altogether our findings demonstrate that N -glyc of TRAIL-R1 promotes TRAIL signaling and restricts virus-mediated inhibition.