Hypoxia-inducible factors (HIFs) and the HIF-dependent cancer hallmarks angiogenesis and metabolic rewiring are well-established drivers of breast cancer aggressiveness, therapy resistance, and poor prognosis. Targeting of HIF and its downstream targets in angiogenesis and metabolism has been unsuccessful so far in the breast cancer clinical setting, with major unresolved challenges residing in target selection, development of robust biomarkers for response prediction, and understanding and harnessing of escape mechanisms. This Review discusses the pathophysiological role of HIFs, angiogenesis, and metabolism in breast cancer and the challenges of targeting these features in patients with breast cancer. Rational therapeutic combinations, especially with immunotherapy and endocrine therapy, seem most promising in the clinical exploitation of the intricate interplay of HIFs, angiogenesis, and metabolism in breast cancer cells and the tumor microenvironment.Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 quality control components (the ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.In aging mice, osteoclast number increases in cortical bone but declines in trabecular bone, suggesting that different mechanisms underlie age-associated bone loss in these 2 compartments. Osteocytes produce the osteoclastogenic cytokine RANKL, encoded by Tnfsf11. Tnfsf11 mRNA increases in cortical bone of aged mice, suggesting a mechanism underlying the bone loss. To address this possibility, we aged mice lacking RANKL in osteocytes. Whereas control mice lost cortical bone between 8 and 24 months of age, mice lacking RANKL in osteocytes gained cortical bone during this period. Mice of both genotypes lost trabecular bone with age. Osteoclasts increased with age in cortical bone of control mice but not in RANKL conditional knockout mice. selleck chemicals llc Induction of cellular senescence increased RANKL production in murine and human cell culture models, suggesting an explanation for elevated RANKL levels with age. Overexpression of the senescence-associated transcription factor Gata4 stimulated Tnfsf11 expression in cultured murine osteoblastic cells. Finally, elimination of senescent cells from aged mice using senolytic compounds reduced Tnfsf11 mRNA in cortical bone. Our results demonstrate the requirement of osteocyte-derived RANKL for age-associated cortical bone loss and suggest that increased Tnfsf11 expression with age results from accumulation of senescent cells in cortical bone.Trapping and manipulating micro-size particles using optical tweezers has contributed to many breakthroughs in biology, materials science, and colloidal physics. However, it remains challenging to extend this technique to a few nanometers particles owing to the diffraction limit and the considerable Brownian motion of trapped nanoparticles. In this work, a nanometric optical tweezer is proposed by using a plasmonic nanocavity composed of the closely spaced silver coated fiber tip and gold film. It is found that the radial vector mode can produce a nano-sized near field with the electric-field intensity enhancement factor over 103 through exciting the plasmon gap mode in the nanocavity. By employing the Maxwell stress tensor formalism, we theoretically demonstrate that this nano-sized near field results in a sharp quasi-harmonic potential well, capable of stably trapping 2 nm quantum dots beneath the tip apex with the laser power as low as 3.7 mW. Further analysis reveals that our nanotweezers can stably work in a wide range of particle-to-tip distances, gap sizes, and operation wavelengths. We envision that our proposed nanometric optical tweezers could be compatible with the tip-enhanced Raman spectroscopy to allow simultaneously manipulating and characterizing single nanoparticles as well as nanoparticle interactions with high sensitivity.The fundamental problem of domain wall (DW) inertia-the property that gives to inertial behaviors remains unclear in the physics of magnetic solitons. To understand its nature as well as to achieve accurate DW positioning and efficient manipulation of domain wall motion (DWM), spin wave (SW) pulse-induced DW transient effect is studied both numerically and theoretically in a magnetic nanostrip. It is shown for the first time that there occurs inevitable deceleration/automotion after SW pulse, which indicates nonzero DW inertia. The induced DWM is revealed to relate to two factors energy storing within DW and out-of-plane tilting of DW. To explain the DWM dynamics, a one-dimensional collective model is developed to account for the excitation of spin wave pulse. The model successfully bridges DW energy, DW tilting and DW displacement and provides descriptions in accordance with numerical findings. It is made clear that the DW automotion hence DW inertia originate from the process of DW relaxation toward equilibrium. The DW inertia is expressed in terms of effective mass and turns out to be a time-dependent function with damping constant α as the governing parameter, which opposes the nature of intrinsic mass. For case containing multiple DWs, the total effective mass is shown to concern the reached velocity and stored energy of DWs instead of the number of DWs, which is against common intuition.