Translational control directed by the eukaryotic translation initiation factor 2 ␣-subunit (eIF2␣) kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation. The GCN2 stress response, conserved from yeast to mammals, is critical for resistance to nutritional deficiencies and for the control of feeding behaviors in rodents. The mouse protein IMPACT has sequence similarities to the yeast YIH1 protein, an inhibitor of GCN2. YIH1 competes with GCN2 for binding to a positive regulator, GCN1. Here, we present evidence that IMPACT is the functional counterpart of YIH1. Overexpression of IM-PACT in yeast lowered both basal and amino acid starvation-induced levels of phosphorylated eIF2␣, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2␣ by GCN2 under leucine starvation conditions, abolishing expression of its downstream target genes, ATF4 (CREB-2) and CHOP (GADD153). IMPACT bound to the minimal yeast GCN1 segment required for interaction with yeast GCN2 and YIH1 and to native mouse GCN1. At the protein level, IMPACT was detected mainly in the brain. IMPACT was found to be abundant in the majority of hypothalamic neurons. Scattered neurons expressing this protein at higher levels were detected in other regions such as the hippocampus and piriform cortex. The abundance of IMPACT correlated inversely with phosphorylated eIF2␣ levels in different brain areas. These results suggest that IMPACT ensures constant high levels of translation and low levels of ATF4 and CHOP in specific neuronal cells under amino acid starvation conditions.

Human ATP-binding cassette (ABC) transporters mediate a critical function in the cell, namely the transport of molecules across lipid membranes. Associated to their ubiquitous tissue distribution, they are key players in cellular homeostasis but also potential causative or contributing factors for many pathologies, including Alzheimer's disease (AD). In the central nervous system (CNS), numerous ABC transporters are present throughout the brain parenchyma and especially at the blood-brain barrier (BBB). AD is a neurodegenerative disorder mainly characterized by extracellular deposition of amyloid-β (Aβ) peptides and intracellular accumulation of hyperphosphorylated forms of tau protein. Besides being degraded via proteolytic and phagocytic processes mediated by brain parenchymal cells, a major mechanism for eliminating cerebral Aβ is through its transport across the BBB into the peripheral blood. In fact, many AD cases are associated with impaired Aβ clearance. Consistently, several studies have recently uncovered important roles for ABC transporters in AD pathophysiology. Hence, this review focuses on the relevance of ABC transporters in CNS homeostasis by highlighting AD as a strong example of the deleterious consequences that might result from the former's altered expression and/or activity in the brain. The potentiality of human ABC transporters as novel pharmacological targets for both the diagnosis and therapeutics of AD is emphasized.

Duchenne muscular dystrophy (DMD) patients exhibit skeletal muscle weakness with continuous cycles of muscle fiber degeneration/regeneration, chronic inflammation, low bone mineral density and increased risks of fracture. Fragility fractures and associated complications are considered as a consequence of the osteoporotic condition in these patients. Here, we aimed to establish the relationship between muscular dystrophy and fracture healing by assessing bone regeneration in mdx mice, a model of DMD with absence of osteoporosis. Our results illustrate that muscle defects in mdx mice impact the process of bone regeneration at various levels. In mdx fracture calluses, both cartilage and bone deposition were delayed followed by a delay in cartilage and bone remodeling. Vascularization of mdx fracture calluses was also decreased during the early stages of repair. Dystrophic muscles are known to contain elevated numbers of macrophages contributing to muscle degeneration. Accordingly, we observed increased macrophage recruitment in the mdx fracture calluses and abnormal macrophage accumulation throughout the process of bone regeneration. These changes in the inflammatory environment subsequently had an impact on the recruitment of osteoclasts and the remodeling phase of repair. Further damage to the mdx muscles, using a novel model of muscle trauma, amplified both the chronic inflammatory response and the delay in bone regeneration. In addition, PLX3397 treatment of mdx mice, a cFMS inhibitor in monocytes, partially rescued the bone repair defect through increasing cartilage deposition and decreasing macrophage number. In conclusion, chronic inflammation in mdx mice contributes to the fracture healing delay and is associated with a decrease in angiogenesis and a transient delay in osteoclast recruitment. By revealing the role of dystrophic muscle in regulating the inflammatory response during bone repair, our results emphasize the implication of muscle in the normal bone repair process and may lead to improved treatment of fragility fractures in DMD patients.

Humans have made such dramatic and permanent changes to Earth's landscapes that much of it is now substantially and irreversibly altered from its preanthropogenic state. Remote islands, until recently isolated from humans, offer insights into how these landscapes evolved in response to human-induced perturbations. However, little is known about when and how remote systems were colonized because archaeological data and historical records are scarce and incomplete. Here, we use a multiproxy approach to reconstruct the initial colonization and subsequent environmental impacts on the Azores Archipelago. Our reconstructions provide unambiguous evidence for widespread human disturbance of this archipelago starting between 700-60+50 and 850-60+60 Common Era (CE), ca. 700 y earlier than historical records suggest the onset of Portuguese settlement of the islands. Settlement proceeded in three phases, during which human pressure on the terrestrial and aquatic ecosystems grew steadily (i.e., through livestock introductions, logging, and fire), resulting in irreversible changes. Our climate models suggest that the initial colonization at the end of the early Middle Ages (500 to 900 CE) occurred in conjunction with anomalous northeasterly winds and warmer Northern Hemisphere temperatures. These climate conditions likely inhibited exploration from southern Europe and facilitated human settlers from the northeast Atlantic. These results are consistent with recent archaeological and genetic data suggesting that the Norse were most likely the earliest settlers on the islands.

Breast cancer is the most common type of cancer affecting women. Despite the good prognosis when detected early, significant challenges remain in the treatment of metastatic breast cancer. The recruitment of the vacuolar H+-ATPase (V-H+-ATPase) to the plasma membrane, where it mediates the acidification of the tumor microenvironment (TME), is a recognized feature involved in the acquisition of a metastatic phenotype in breast cancer. Therefore, inhibitors of this pump have emerged as promising anticancer drugs. Lactoferrin (Lf) is a natural pro-apoptotic iron-binding glycoprotein with strong anticancer activity whose mechanism of action is not fully understood. Here, we show that bovine Lf (bLf) preferentially induces apoptosis in the highly metastatic breast cancer cell lines Hs 578T and MDA-MB-231, which display a prominent localisation of V-H+-ATPase at the plasma membrane, but not in the lowly metastatic T-47D or in the non-tumorigenic MCF-10-2A cell lines. We also demonstrate that bLf decreases the extracellular acidification rate and causes intracellular acidification in metastatic breast cancer cells and, much like the well-known proton pump inhibitors concanamycin A and bafilomycin A1, inhibits V-H+-ATPase in sub-cellular fractions. These data further support that bLf targets V-H+-ATPase and explain the selectivity of bLf for cancer cells, especially for highly metastatic breast cancer cells. Altogether, our results pave the way for more rational in vivo studies aiming to explore this natural non-toxic compound for metastatic breast cancer therapy.

The nuclear envelope (NE) is the central organizing unit of the eukaryotic cell serving as a genome protective barrier and mechanotransduction interface between the cytoplasm and the nucleus. The NE is mainly composed of a nuclear lamina and a double membrane connected at specific points where the nuclear pore complexes (NPCs) form. Physiological aging might be generically defined as a functional decline across lifespan observed from the cellular to organismal level. Therefore, during aging and premature aging, several cellular alterations occur, including nuclear‐specific changes, particularly, altered nuclear transport, increased genomic instability induced by DNA damage, and telomere attrition. Here, we highlight and discuss proteins associated with nuclear transport dysfunction induced by aging, particularly nucleoporins, nuclear transport factors, and lamins. Moreover, changes in the structure of chromatin and consequent heterochromatin rearrangement upon aging are discussed. These alterations correlate with NE dysfunction, particularly lamins’ alterations. Finally, telomere attrition is addressed and correlated with altered levels of nuclear lamins and nuclear lamina‐associated proteins. Overall, the identification of molecular mechanisms underlying NE dysfunction, including upstream and downstream events, which have yet to be unraveled, will be determinant not only to our understanding of several pathologies, but as here discussed, in the aging process.

We present a European Union/European Economic Area-wide overview of the changes in consumption of antibacterials for systemic use (ATC J01) in the community between 2019 and 2020 as reported to the European Surveillance of Antimicrobial Consumption Network. Overall antibiotic consumption decreased by 18.3% between 2019 and 2020, the largest annual decrease in the network's two-decade history. We observed a strong association between the level of community antibiotic consumption in 2019 and the size of the decrease between 2019 and 2020.

The production of highly specialized spermatozoa from undifferentiated spermatogonia is a strictly organized and programmed process requiring extensive restructuring of the entire cell. One of the most remarkable cellular transformations accompanying the various phases of spermatogenesis is the profound remodelling of the nuclear architecture, in which the nuclear envelope (NE) seems to be crucially involved. In recent years, several proteins from the distinct layers forming the NE (i.e. the inner and outer nuclear membranes as well as the nuclear lamina) have been associated with meiosis and/or spermiogenesis in different mammalian species. Among these are A-and B-type lamins, Dpy-19-like protein 2 (DPY19L2), lamin B receptor (LBR), lamina-associated polypeptide 1 (LAP1), LAP2/emerin/MAN1 (LEM) domain-containing proteins, spermatogenesis-associated 46 (SPATA46) and diverse elements of the linker of nucleoskeleton and cytoskeleton (LINC) complex, namely Sad-1/UNC-84 homology (SUN) and Klarsicht/ANC-1/Syne-1 homology (KASH) domain-containing proteins. Herein, we summarize the current state of the art on the cellular and subcellular distribution of NE proteins expressed during mammalian spermatogenesis, and discuss the latest research developments regarding their testis-specific functions. This review provides a comprehensive and innovative overview of the NE network as a regulatory platform and as an essential determinant of efficient meiotic chromosome recombination as well as spermiogenesis-associated nuclear remodelling and differentiation in mammalian male germline cells. Thus, this review provides important novel insights on the biological relevance of NE proteins for male fertility.