A proteomic atlas of senescence-associated secretomes for aging biomarker development.

The senescence-associated secretory phenotype (SASP) has recently emerged as a driver of and promising therapeutic target for multiple age-related conditions, ranging from neurodegeneration to cancer. The complexity of the SASP, typically assessed by a few dozen secreted proteins, has been greatly underestimated, and a small set of factors cannot explain the diverse phenotypes it produces in vivo. Here, we present the "SASP Atlas," a comprehensive proteomic database of soluble proteins and exosomal cargo SASP factors originating from multiple senescence inducers and cell types. Each profile consists of hundreds of largely distinct proteins but also includes a subset of proteins elevated in all SASPs. Our analyses identify several candidate biomarkers of cellular senescence that overlap with aging markers in human plasma, including Growth/differentiation factor 15 (GDF15), stanniocalcin 1 (STC1), and serine protease inhibitors (SERPINs), which significantly correlated with age in plasma from a human cohort, the Baltimore Longitudinal Study of Aging (BLSA). Our findings will facilitate the identification of proteins characteristic of senescence-associated phenotypes and catalog potential senescence biomarkers to assess the burden, originating stimulus, and tissue of origin of senescent cells in vivo.

The power of proteomics to monitor senescence-associated secretory phenotypes and beyond: toward clinical applications.

INTRODUCTION: Cellular senescence is a rapidly growing field with potential relevance for the treatment of multiple human diseases. In the last decade, cellular senescence and the senescence-associated secretory phenotype (SASP) have emerged as central drivers of aging and many chronic diseases, including cancer, neurodegeneration, heart disease and osteoarthritis. Major efforts are underway to develop drugs that selectively eliminate senescent cells (senolytics) or alter the SASP (senomorphics) to treat age-related diseases in humans. The translation of senescence-targeting therapies into humans is still in early stages. Nonetheless, it is clear that proteomic approaches will facilitate the discovery of important SASP proteins, development of senescence- and SASP-derived biomarkers, and identification of therapeutic targets for senolytic and senomorphic drugs. AREAS COVERED: We review recent proteomic studies of cellular senescence and their translational relevance and, particularly, characterization of the secretory phenotype and preclinical development of biomarkers (from 2008-2020, PubMed). We focus on emerging areas, such as the heterogeneity of senescent cells and the SASP, extracellular vesicles released by senescent cells, and validating biomarkers of aging in vivo. EXPERT OPINION: Proteomic and multi-omic approaches will be important for the development of senescence-based biomarkers to facilitate and monitor future therapeutic interventions that target senescent cells.

Role of immune cells in the removal of deleterious senescent cells.

Cellular senescence is an essentially irreversible arrest of cell proliferation coupled to a complex senescence-associated secretory phenotype (SASP). The senescence arrest prevents the development of cancer, and the SASP can promote tissue repair. Recent data suggest that the prolonged presence of senescent cells, and especially the SASP, could be deleterious, and their beneficial effects early in life can become maladaptive such that they drive aging phenotypes and pathologies late in life. It is therefore important to develop strategies to eliminate senescent cells. There are currently under development or approved several immune cell-based therapies for cancer, which could be redesigned to target senescent cells. This review focuses on this possible use of immune cells and discusses how current cell-based therapies could be used for senescent cell removal.

Mitosis in neurons: Roughex and APC/C maintain cell cycle exit to prevent cytokinetic and axonal defects in Drosophila photoreceptor neurons.

The mechanisms of cell cycle exit by neurons remain poorly understood. Through genetic and developmental analysis of Drosophila eye development, we found that the cyclin-dependent kinase-inhibitor Roughex maintains G1 cell cycle exit during differentiation of the R8 class of photoreceptor neurons. The roughex mutant neurons re-enter the mitotic cell cycle and progress without executing cytokinesis, unlike non-neuronal cells in the roughex mutant that perform complete cell divisions. After mitosis, the binucleated R8 neurons usually transport one daughter nucleus away from the cell body into the developing axon towards the brain in a kinesin-dependent manner resembling anterograde axonal trafficking. Similar cell cycle and photoreceptor neuron defects occurred in mutants for components of the Anaphase Promoting Complex/Cyclosome. These findings indicate a neuron-specific defect in cytokinesis and demonstrate a critical role for mitotic cyclin downregulation both to maintain cell cycle exit during neuronal differentiation and to prevent axonal defects following failed cytokinesis.

An audit of admissions and mortality of orthopedic indoor patients in a tertiary care hospital of India.

INTRODUCTION: Mortality in orthopaedics is different in underdeveloped, developing and developed countries depending on the health, orthopaedic and trauma care services, education status and social awareness. Analysis of mortality and causes of death is an important step to identify the risk factor. Such study is invaluable for epidemiological monitoring and health care planning. METHODS: Between September 2015 to August 2018 demographic data, timing and primary diagnosis of both mortality and admission were collected retrospectively in a leading tertiary care hospital in the city of Mumbai, India. RESULTS: Total admissions of 10,937 in the 3-year period with increased average monthly admission in the month of June, July and August. Trauma to be most common cause of admission and death and Road traffic accident to be the most common cause of trauma followed by slip and fall. The death rate was 0.55 per 100 admissions per year. In males most common age group was 18-60 years and in females above 60 years of age. CONCLUSION: There is a link of increased admission rate in the monsoon months (rainy season) in India and road traffic accident and slip and fall. So accident prevention and health care planning and management of trauma victim, improvement of quality of life of general population will reduce trauma and related complications.

Effect of Surface Texture on Pinhole Formation in SiOx-Based Passivated Contacts for High-Performance Silicon Solar Cells.

High-efficiency silicon solar cells rely on some form of passivating contact structure to reduce recombination losses at the crystalline silicon surface and losses at the metal/Si contact interface. One such structure is polycrystalline silicon (poly-Si) on oxide, where heavily doped poly-Si is deposited on a SiOx layer grown directly on the crystalline silicon (c-Si) wafer. Depending on the thickness of the SiOx layer, the charge carriers can cross this layer by tunneling (<2 nm SiOx thickness) or by direct conduction through disruptions in the SiOx, often referred to as pinholes, in thicker SiOx layers (>2 nm). In this work, we study structures with tunneling- or pinhole-like SiOx contacts grown on pyramidally textured c-Si wafers and expose variations in the SiOx layer properties related to surface morphology using electron-beam-induced current (EBIC) imaging. Using EBIC, we identify and mark regions with potential pinholes in the SiOx layer. We further perform high-resolution transmission electron microscopy on the same areas, thus allowing us to directly correlate locally enhanced carrier collection with variations in the structure of the SiOx layer. Our results show that the pinholes in the SiOx layer preferentially form in different locations based on the annealing conditions used to form the device. With greater understanding of these processes and by controlling the surface texture geometry, there is potential to control the size and spatial distribution of oxide disruptions in silicon solar cells with poly-Si on oxide-type contacts; usually, this is a random phenomenon on polished or planar surfaces. Such control will enable us to consistently produce high-efficiency devices with low recombination currents and low junction resistances using this contact structure.

Senescent cells promote tissue NAD+ decline during ageing via the activation of CD38+ macrophages.

Declining tissue nicotinamide adenine dinucleotide (NAD) levels are linked to ageing and its associated diseases. However, the mechanism for this decline is unclear. Here, we show that pro-inflammatory M1-like macrophages, but not naive or M2 macrophages, accumulate in metabolic tissues, including visceral white adipose tissue and liver, during ageing and acute responses to inflammation. These M1-like macrophages express high levels of the NAD-consuming enzyme CD38 and have enhanced CD38-dependent NADase activity, thereby reducing tissue NAD levels. We also find that senescent cells progressively accumulate in visceral white adipose tissue and liver during ageing and that inflammatory cytokines secreted by senescent cells (the senescence-associated secretory phenotype, SASP) induce macrophages to proliferate and express CD38. These results uncover a new causal link among resident tissue macrophages, cellular senescence and tissue NAD decline during ageing and offer novel therapeutic opportunities to maintain NAD levels during ageing.

Clearance of apoptotic corpses.

Apoptotic corpses can be engulfed and cleared by many other cell types in addition to 'professional' phagocytes such as macrophage. Studies of several organisms have contributed to the understanding of apoptotic corpse engulfment. Two partially redundant engulfment pathways have been characterized that act even in non-professional phagocytes to promote corpse engulfment. This review summarizes some recent progress in signaling by these pathways, including the exposure of eat-me-signals on apoptotic cells, and insights from Drosophila on the roles of the bridging receptor Six Microns Under, the non-receptor tyrosine kinase Shark, and store-operated calcium release in the Draper/Ced-1 pathway of corpse recognition and internalization. The mechanism of apoptotic phagosome maturation is outlined, and possible connections between corpse engulfment and proliferation, cell competition, and immunity are discussed.

Effect of Crystallographic Orientation and Nanoscale Surface Morphology on Poly-Si/SiOx Contacts for Silicon Solar Cells.

High-efficiency crystalline silicon (Si) solar cells require textured surfaces for efficient light trapping. However, passivation of a textured surface to reduce carrier recombination is difficult. Here, we relate the electrical properties of cells fabricated on a KOH-etched, random pyramidal-textured Si surface to the nanostructure of the passivated contact and the textured surface morphology. The effects of both microscopic pyramidal morphology and nanoscale surface roughness on passivated contacts consisting of polycrystalline Si (poly-Si) deposited on top of an ultrathin, 1.5-2.2 nm, SiOx layer are investigated. Using atomic force microscopy, we show a pyramid face, which is predominantly a Si(111) plane to be significantly rougher than a polished Si(111) surface. This roughness results in a nonuniform SiOx layer as determined by transmission electron microscopy of a poly-Si/SiOx contact. Our device measurements also show an overall more resistive and hence a thicker SiOx layer over the pyramidal surface as compared to a polished Si(111) surface, which we relate to increased surface roughness. Using electron-beam-induced current measurements of poly-Si/SiOx contacts, we further show that the SiOx layer near the pyramid valleys is preferentially more conducting and hence likely thinner than over pyramid tips, edges, and faces. Hence, both the microscopic pyramidal morphology and nanoscale roughness lead to a nonuniform SiOx layer, thus leading to poor poly-Si/SiOx contact passivation. Finally, we report >21% efficient and ≥80% fill-factor front/back poly-Si/SiOx solar cells on both single-side and double-side textured wafers without the use of transparent conductive oxide layers, and show that the poorer contact passivation on a textured surface is limited to boron-doped poly-Si/SiOx contacts.

Tumor evolution: Multiple induction mechanisms for cell competition.

Tumor cells often differ genetically from normal cells and from one another. Competitive interactions can occur between genetically-distinct cells, and recent studies highlight multiple examples where cell competition initiates using distinct pathways.

Ribosomal Protein S12e Has a Distinct Function in Cell Competition.

Wild-type Drosophila cells can remove cells heterozygous for ribosomal protein mutations (known as "Minute" mutant cells) from genetic mosaics, a process termed cell competition. The ribosomal protein S12 was unusual because cells heterozygous for rpS12 mutations were not competed by wild-type, and a viable missense mutation in rpS12 protected Minute cells from cell competition with wild-type cells. Furthermore, cells with Minute mutations were induced to compete with one another by altering the gene dose of rpS12, eliminating cells with more rpS12 than their neighbors. Thus RpS12 has a special function in cell competition that defines the competitiveness of cells. We propose that cell competition between wild-type and Minute cells is initiated by a signal of ribosomal protein haploinsufficiency mediated by RpS12. Since competition between cells expressing different levels of Myc did not require RpS12, other kinds of cell competition may be initiated differently.

Mutations in ribosomal proteins: Apoptosis, cell competition, and cancer.

Mutations affecting multiple ribosomal proteins are implicated in cancer. Using genetic mosaics in the fruit fly Drosophila, we describe 3 apoptotic mechanisms that affect Rp/Rp homozygous mutant cells, Rp/+ heterozygous cells, or Rp/+ heterozygous cells in competition with nearby wild type cells, and discuss how apoptosis might be related to cancer predisposition.

Local Cell Death Changes the Orientation of Cell Division in the Developing Drosophila Wing Imaginal Disc Without Using Fat or Dachsous as Orienting Signals.

Drosophila imaginal disc cells exhibit preferred cell division orientations according to location within the disc. These orientations are altered if cell death occurs within the epithelium, such as is caused by cell competition or by genotypes affecting cell survival. Both normal cell division orientations, and their orientations after cell death, depend on the Fat-Dachsous pathway of planar cell polarity (PCP). The hypothesis that cell death initiates a planar polarity signal was investigated. When clones homozygous for the pineapple eye (pie) mutation were made to initiate cell death, neither Dachsous nor Fat was required in pie cells for the re-orientation of nearby cells, indicating a distinct signal for this PCP pathway. Dpp and Wg were also not needed for pie clones to re-orient cell division. Cell shapes were evaluated in wild type and mosaic wing discs to assess mechanical consequences of cell loss. Although proximal wing disc cells and cells close to the dorso-ventral boundary were elongated in their preferred cell division axes in wild type discs, cell shapes in much of the wing pouch were symmetrical on average and did not predict their preferred division axis. Cells in pie mutant clones were slightly larger than their normal counterparts, consistent with mechanical stretching following cell loss, but no bias in cell shape was detected in the surrounding cells. These findings indicate that an unidentified signal influences PCP-dependent cell division orientation in imaginal discs.

Oriented cell division as a response to cell death and cell competition.

The imaginal disc epithelia that give rise to the adult ectoderm of Drosophila can compensate to produce normal adult organs after damage. We looked at the local response to cell death by using two genetic methods to elevate cell death rates. During cell competition, sporadic cell death occurs predictably along the boundaries between populations of competing wild-type and "Minute" cells (M/+). Boundaries between M/+ and wild-type populations show an unusual degree of mixing, associated with mitotic reorientation of wild-type cells toward M/+ territory that they take over. Apoptosis of M/+ cells was the cue, and reoriented mitosis required the planar cell polarity genes dachsous, fat, and atrophin. Clones mutated for pineapple eye, an essential gene, elevate apoptosis by a noncompetitive mechanism. Mitosis was also reoriented near cells mutant for pineapple eye, likewise dependent on the planar cell polarity genes. These findings show that planar cell polarity genes are required for responses to cell death. Oriented mitosis may help maintain morphology as dividing cells replace those that have been lost.

Smoking interferes with the prognosis of dental implant treatment: a systematic review and meta-analysis.

AIM: This systematic literature review was performed to investigate if smoking interferes with the prognosis of implants with and without accompanying augmentation procedures compared with non-smokers. METHODS: A systematic electronic and handsearch (articles published between 1989 and 2005; English and German language; search terms "dental or oral implants and smoking"; "dental or oral implants and tobacco") was performed to identify publications providing numbers of failed implants, related to the numbers of smokers and non-smokers for meta-analysis. Publications providing statistically examined data of implant failures or biologic complications among smokers compared with non-smokers were included for systematic review. RESULTS: Of 139 publications identified, 29 were considered for meta-analysis and 35 for systematic review. Meta-analysis revealed a significantly enhanced risk for implant failure among smokers [implant-related odds ratio (OR) 2.25, confidence interval (CI(95%)) 1.96-2.59; patient-related OR 2.64; CI(95%) 1.70-4.09] compared with non-smokers, and for smokers receiving implants with accompanying augmentation procedures (OR 3.61; CI(95%) 2.26-5.77, implant related). The systematic review indicated significantly enhanced risks of biologic complications among smokers. Five studies revealed no significant impact of smoking on prognosis of implants with particle-blasted, acid-etched or anodic oxidized surfaces. CONCLUSION: Smoking is a significant risk factor for dental implant therapy and augmentation procedures accompanying implantations.

Bee-eaters ( Merops orientalis) respond to what a predator can see.

Two sets of experiments are reported that show that the small green bee-eater ( Merops orientalis, a small tropical bird) can appreciate what a predator can or cannot see. Bee-eaters avoid entering the nest in the presence of a potential nest predator. In the first set of experiments bee-eaters entered the nest more frequently when the predator was unable to see the nest from its position, as compared to an approximately equidistant position from which the nest could be seen. In the second set of experiments bee-eaters entered the nest more frequently when the predator was looking away from the nest. The angle of gaze from the nest was associated significantly positively with the probability of entering the nest whereas the angle from the bird was not. Birds showed considerable flexibility as well as individual variation in the possible methods of judging the predator's position and direction of gaze.