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In this paper, we address the problem of detecting a Noise-Like Jammer (NLJ) that does not quickly transmit all the available power but it gradually increases the transmitted power. This control strategy would prevent conventional electronic counter-countermeasures from revealing the presence of a noise power discontinuity in the window under test. As a consequence, the radar system under attack becomes blind requiring a reaction by an expert operator. In order to face such a situation, we devise two innovative NLJ detection architectures by assuming at the design stage specific models for the NLJ power variation. The first model is based on a linear variation law over the observation time, whereas in the second model, the NLJ power experiences unconstrained fluctuations in the window under test. Under these hypotheses, we resort to ad hoc modifications of the generalized likelihood ratio test, where the unknown parameters are replaced by suitable estimates obtained through iterative procedures. The performance analysis, carried out using synthetic data, shows the effectiveness and superiority of the proposed detectors over the conventional approach.

Manual palpation is a crucial medical procedure that relies on surface examination to detect internal tissue abnormalities, heavily reliant on healthcare professionals’ expertise and tactile sensitivity. To tackle these issues, smart palpation systems based on electrical or optical sensors have been developed to perform quantitative tactile measurements, crucial for identifying various solid tumors, including breast and prostate cancer by assessing tissue mechanical properties. In this context, fiber Bragg gratings (FBGs) are emerging as a an ideal candidate for tactile sensing due to their advantages (e.g., high metrological properties, multiplexing capacity, and easy packaging). This study explores the benefits of FBG and 3-D printing to develop a tactile sensor for tissue palpation. First, an optimization of the design of the sensing core of a previously developed probe was conducted through finite element analysis. The novel structure addresses the primary limitation of the previous solution, where nonuniform strain distribution on the encapsulated FBG causes compression on the grating with high risk of bending and breakage. In contrast, the modeled geometry ensures FBG elongation during tissue palpation. A 3-D printing and characterization of the proposed solution was carried out to investigate the response of the enclosed FBG when pushed against different materials showing promising results in discriminating tissues according to their mechanical properties: the more rigid the indented substrate, the higher the sensor output. This property will be fundamental for enhancing early tumor detection through superficial tissue palpation, advancing the efficacy of prevention measures.

Proteins are particularly prone to aggregation immediately after release from the ribosome, and it is therefore important to elucidate the role of chaperones during these key steps of protein life. The Hsp70 and trigger factor (TF) chaperone systems interact with nascent proteins during biogenesis and immediately post-translationally. It is unclear, however, whether these chaperones can prevent formation of soluble and insoluble aggregates. Here, we address this question by monitoring the solubility and structural accuracy of globin proteins biosynthesized in an Escherichia colicell-free system containing different concentrations of the bacterial Hsp70 and TF chaperones. We find that Hsp70 concentrations required to grant solubility to newly synthesized proteins are extremely sensitive to client-protein sequence. Importantly, Hsp70 concentrations yielding soluble client proteins are insufficient to prevent formation of soluble aggregates. In fact, for some aggregation-prone protein variants, avoidance of soluble-aggregate formation demands Hsp70 concentrations that exceed cellular levels in E. coli. In all, our data highlight the prominent role of soluble aggregates upon nascent-protein release from the ribosome and show the limitations of the Hsp70 chaperone system in the case of highly aggregation-prone proteins. These results demonstrate the need to devise better strategies to prevent soluble-aggregate formation upon release from the ribosome.

The prevention and management of ocular surface infections is still one of the great challenges for ophthalmologists. The spread of antimicrobial resistance makes it necessary to use antiseptic substances with a broad antimicrobial spectrum. Polyhexamethylene biguanide hydrochloride (Polyhexanide, PHMB) is a broad-spectrum antiseptic with excellent tolerance and a low-risk profile. Its physicochemical action on the phospholipid membrane and DNA replication or repair mechanism, prevents or impedes the development of resistant bacterial strains. PHMB revealed its effective against numerous organisms like viruses, Gram-negative and Gram-positive bacteria, and fungi. Polyhexanide is commonly used as preservative in commercially available disinfecting solutions for contact lens care and in ophthalmic formulations at different concentrations ranging from 1 µg/ml to 50 µg/ml. The administration of 0.02% (200 µg/ml) PHMB is often the first-line therapy of Acanthamoeba keratitis. However, to date, only one close-out randomized controlled study tested the efficacy of 0.02% PHMB in Acanthamoeba keratitis and a phase III study is still ongoing. This paper reviews the antiseptic agent PHMB, focusing on biochemical mechanisms, safety profile and applications in ophthalmology.

This article addresses the challenge of identifying the polarimetric covariance matrix (PCM) structures associated with a polarimetric synthetic aperture radar (SAR) image. Interestingly, such information can be used, for instance, to improve the scene interpretation or to enhance the performance of (possibly PCM-based) segmentation algorithms as well as other kinds of methods. To this end, a general framework to solve a multiple hypothesis test is introduced with the aim to detect and classify contextual spatial variations in polarimetric SAR images. Specifically, under the null hypothesis, only one unknown structure is assumed for data belonging to a two-dimensional spatial sliding window, whereas under each alternative hypothesis, data are partitioned into subsets sharing different PCM structures. The problem of partition estimation is solved by resorting to hidden random variables representative of covariance structure classes and the expectation–maximization algorithm. The effectiveness of the proposed detection strategies is demonstrated on both simulated and real polarimetric SAR data also in comparison with existing classification algorithms.

Cryogenic phonon detectors with transition-edge sensors achieve the best sensitivity to sub-GeV/c2dark matter interactions with nuclei in current direct detection experiments. In such devices, the temperature of the thermometer and the bias current in its readout circuit need careful optimization to achieve optimal detector performance. This task is not trivial and is typically done manually by an expert. In our work, we automated the procedure with reinforcement learning in two settings. First, we trained on a simulation of the response of three Cryogenic Rare Event Search with Superconducting Thermometers (CRESST) detectors used as a virtual reinforcement learning environment. Second, we trained live on the same detectors operated in the CRESST underground setup. In both cases, we were able to optimize a standard detector as fast and with comparable results as human experts. Our method enables the tuning of large-scale cryogenic detector setups with minimal manual interventions.

Hyperspectral target detection is a task of primary importance in remote sensing since it allows for location and discrimination of target features. To this end, the reflectance maps, which contain the spectral signatures and related abundances of the materials in the observed scene, are often used. However, due to the low spatial resolution of most hyperspectral sensors, targets occupy a fraction of the pixel and, hence, the spectra of different sub-pixel targets (including the background spectrum) are mixed together within the same pixel. To solve this issue, in this paper, we adopt a generalized replacement model accounting for multiple sub-pixel target spectra and formulate the detection problem at hand as a binary hypothesis test where under the alternative hypothesis the target is modeled in terms of a linear combination of endmembers whose coefficients also account for the presence of the background. Then, we devise detection architectures based upon the generalized likelihood ratio test where the unknown parameters are suitably estimated through procedures inspired by the maximum likelihood approach. The performances of the proposed decision schemes are evaluated by means of both synthetic as well as real data and compared with other counterparts by showing the effectiveness of the proposed procedure.

Gibbons are the most speciose family of living apes, characterized by a diverse chromosome number and rapid rate of large-scale rearrangements. Here we performed single-cell template strand sequencing (Strand-seq), molecular cytogenetics, and deep in silico analysis of a southern white-cheeked gibbon genome, providing the first comprehensive map of 238 previously hidden small-scale inversions. We determined that more than half are gibbon specific, at least fivefold higher than shown for other primate lineage-specific inversions, with a significantly high number of small heterozygous inversions, suggesting that accelerated evolution of inversions may have played a role in the high sympatric diversity of gibbons. Although the precise mechanisms underlying these inversions are not yet understood, it is clear that segmental duplication–mediated NAHR only accounts for a small fraction of events. Several genomic features, including gene density and repeat (e.g., LINE-1) content, might render these regions more break-prone and susceptible to inversion formation. In the attempt to characterize interspecific variation between southern and northern white-cheeked gibbons, we identify several large assembly errors in the current GGSC Nleu3.0/nomLeu3 reference genome comprising more than 49 megabases of DNA. Finally, we provide a list of 182 candidate genes potentially involved in gibbon diversification and speciation.

The relation between co- and post-translational protein folding and aggregation in the cell is poorly understood. Here, we employ a combination of fluorescence anisotropy decays in the frequency domain, fluorescence-detected solubility assays, and NMR spectroscopy to explore the role of the ribosome in protein folding within a biologically relevant context. First, we find that a primary function of the ribosome is to promote cotranslational nascent-protein solubility, thus supporting cotranslational folding even in the absence of molecular chaperones. Under these conditions, however, only a fraction of the soluble expressed protein is folded and freely tumbling in solution. Hence, the ribosome alone is insufficient to guarantee quantitative formation of the native state of the apomyoglobin (apoMb) model protein. Right after biosynthesis, nascent chains encoding apoMb emerge from the ribosomal exit tunnel and undergo a crucial irreversible post-translational kinetic partitioning between further folding and aggregation. Mutational analysis in combination with protein-expression kinetics and NMR show that nascent proteins can attain their native state only when the relative rates of soluble and insoluble product formation immediately upon release from the ribosome are tilted in favor of soluble species. Finally, the outcome of the above immediately post-translational kinetic partitioning is much more sensitive to amino acid sequence perturbations than the native fold, which is rather mutation-insensitive. Hence, kinetic channeling of nascent-protein conformation upon release from the ribosome may be a major determinant of evolutionary pressure.

Objective: To evaluate the morphologic and functional outcomes of different optical coherence tomography (OCT) patterns of myopic foveoschisis after vitrectomy with Inner Limiting Membrane (ILM) peeling. Methods: In this prospective non-randomised study, 62 consecutive eyes with Myopic Foveoschisis were categorised into three groups according to OCT pattern: retinoschisis type (Rt) Group (23/62), foveal detachment type (FDt) Group (20/62) and macular hole type (MHt) Group (19/62). All patients underwent 25-Gauge vitrectomy and ILM peeling. Air or gas tamponade was used. All patients were observed at month 1, 2, 4 and 6 after surgery. Main outcomes measures: surgical success as resolution of myopic foveoschisis, central retinal thickness (CRT), IS/OS junction recovery and best-corrected visual acuity (BCVA) measurement. Any complication was reported. Results: In all eyes OCT showed a resolution of the retinoschisis, foveal detachment and macular hole pattern, respectively. CRT significantly decreased in all Groups (p?<?.001), mainly in MHt. IS/OS junction recovery was mainly observed in MHt. BCVA significantly increased in all Groups (p?<?.01). A functional gain =2 Snellen lines occurred in 70, 85 and 68% in the Rt, FDt and MHt Group, respectively. Final BCVA was correlated with preoperative BCVA (R0.74, p?<?0.0001), postoperative CRT (R-0.49, p?<?0.0001), and the recovery of IS/OS junction at 6 months (R0.76, p?<?0.0001). Few postoperative complications occurred. Conclusions: Vitrectomy with ILM peeling results in favourable anatomic and functional outcomes for different patterns of myopic foveoschisis.

Double minutes (dmin), homogeneously staining regions, and ring chromosomes are vehicles of gene amplification in cancer. The underlying mechanism leading to their formation as well as their structure and function in acute myeloid leukemia (AML) remain mysterious. We combined a range of high-resolution genomic methods to investigate the architecture and expression pattern of amplicons involving chromosome band 8q24 in 23 cases of AML (AML-amp). This revealed that different MYC-dmin architectures can coexist within the same leukemic cell population, indicating a step-wise evolution rather than a single event origin, such as through chromothripsis. This was supported also by the analysis of the chromothripsis criteria, that poorly matched the model in our samples. Furthermore, we found that dmin could evolve toward ring chromosomes stabilized by neocentromeres. Surprisingly, amplified genes (mainly PVT1) frequently participated in fusion transcripts lacking a corresponding DNA template. We also detected a significant overexpression of the circular RNA of PVT1(circPVT1) in AML-amp cases versus AML with a normal karyotype. Our results show that 8q24 amplicons in AML are surprisingly plastic DNA structures with an unexpected association to novel fusion transcripts and circular RNAs.

For many years, inversions have been proposed to be a direct driving force in speciation since they suppress recombination when heterozygous. Inversions are the most common large-scale differences among humans and great apes. Nevertheless, they represent large events easily distinguishable by classical cytogenetics, whose resolution, however, is limited. Here, we performed a genome-wide comparison between human, great ape, and macaque genomes using the net alignments for the most recent releases of genome assemblies. We identified a total of 156 putative inversions, between 103 kb and 91 Mb, corresponding to 136 human loci. Combining literature, sequence, and experimental analyses, we analyzed 109 of these loci and found 67 regions inverted in one or multiple primates, including 28 newly identified inversions. These events overlap with 81 human genes at their breakpoints, and seven correspond to sites of recurrent rearrangements associated with human disease. This work doubles the number of validated primate inversions larger than 100 kb, beyond what was previously documented. We identified 74 sites of errors, where the sequence has been assembled in the wrong orientation, in the reference genomes analyzed. Our data serve two purposes: First, we generated a map of evolutionary inversions in these genomes representing a resource for interrogating differences among these species at a functional level; second, we provide a list of misassembled regions in these primate genomes, involving over 300 Mb of DNA and 1978 human genes. Accurately annotating these regions in the genome references has immediate applications for evolutionary and biomedical studies on primates.

A new species of Stygarctidae, belonging to the genus Pseudostygarctus McKirdy et al., 1976, Pseudostygarctus apuliae, was found in subtidal sediments of Porto Colombo, near Bari (Adriatic Sea) and is described. The new species has intermediate characters between P. triungulatus McKirdy et al., 1976, and P. mirabilis de Zio Grimaldi et al., 1998. Its major distinctive traits are: the dorsal plates morphology and the cuticle sculpture.

Quantitative samples of sediment for the study of the meiofau-na were collected monthly beweenMar1996 andFeb1997 from a 7-m-deep site in the Meloria Shoals, Livorno Italy. In the Tuscan Shoals, 16 species of tardigrades were found belonging to the families Stygarctidae, Halechiniscidae, and Batillipedidae. Megastygarctides orbiculatus and Actinarctus doryphorus are reported for the first time in the Mediterranean Sea, and a re-description of Batillipes similis is proposed. Global density of the Tardigrada population fluctuated between 8 ind./10 cm2 in May 1996 and 285 ind./10 cm2 in January 1997. The lowest value of the Shannon-Wiener biodiversity index (H' = 1.09) was found in September 1996, whereas the highest score (H' = 2.46) was obtained inMar1996. Pielou's evenness index (J) fluctuated between 0.40 and 0.88, values attained in January 1997 andMar1996, respectively. The study confirms the notion that the organogenic detritus of the Shoals represents a very favourable environment for meiofaunal organisms in general, and Tardigrada in particular.

Congenital sinuses or fistulas of the upper lip are extremely rare malformations often associated with other congenital anomalies, mainly cleft lip and palate. There are very few cases described in the literature, and the aetiology of this rare occurrence remains obscure. This article present a case of congenital upper lip fistula located in the midline of the philtrum of a 11-year old girl. The authors discuss the major embryological theories about pathogenesis of upper lip fistulas: the “fusion theory”, the “invagination theory”, and the “merging theory”. Finally, we propose that early ectodermal inclusion events in the medial fusion area between the two medial nasal processes, during the formation of the intermaxillary process, could be involved in the embryopathogenesis of the midline fistula of the upper lip.

In this paper, we document the pattern of unpaid domestic and care work, disaggregated on the basis of the type of work and the care recipient, and its partial correlation with subjective well-being as measured by reported life satisfaction. We explore gender-specific effects since domestic and unpaid work has an intrinsic relational dimension that, at least in the current Italian society, has an important gender-specific component. The data used come from the 2012 Survey on the Economic and Social Conditions in the Modena District (ICESmo3) which is a unique dataset that contains disaggregated data on unpaid work. In particular, this dataset allows us to look at the correlations between the different types of unpaid work and reported life satisfaction. The overall picture that emerges from the data is one where unpaid work within the household is more likely to be conducive of well-being if it is more likely to be genuinely voluntary and intrinsically motivated. Although we must admit that this conclusion is highly speculative, we think it is a good starting point for further analyses in this regard.

Background:The atherosclerotic plaque is a complex niche composed of immune cells including T cells and macrophages as well as vascular smooth muscle cells. How T cells interact with the plaque microenvironment is not well understood.Objective:To map the crosstalk between T cells, macrophages, and smooth muscle cells.Methods/Results:We performed single cell RNAseq using the 10x transcriptomics platform in coronary plaque samples from 12 patients, who underwent heart transplantation. We found a high proportion of macrophages as well as T cells, many of which display a memory phenotype that was confirmed by immunohistochemistry. Ligand-receptor computational analysis demonstrated significant cross talk between T cells, macrophages, and smooth muscle cells. One cytokine of interest is amphiregulin (AREG), which has been shown to mediate tissue healing and fibrosis. Of note, AREG expression appears to increase as coronary plaques progress from early lipid-rich stages to more advanced stages. To elucidate the effects of AREG on smooth muscle cells, we treated human coronary artery smooth muscle cells (hCASMCs) in vitro with recombinant AREG and found increased cell proliferation compared to control (P<0.001). Bulk RNAseq profiling of hCASMCs showed activation of pathways that promote inflammation, proliferation, and fibrosis (Figure 1).Conclusion:Taken together, our findings suggest that cross talk between T cells and smooth muscle cells, partially through AREG production by T cells, may contribute to plaque progression.

Background:Atherosclerosis is considered a chronic inflammatory disorder characterized by the presence of T cells and macrophages in the plaque. Given that T cells are the master regulators of the immune system, the possible role of T cells in mediating disease warrants further investigation.Objective:To map the T cell transcriptome in coronary artery plaque.Methods/Results:Using single cell RNAseq, we mapped the transcriptome of immune cells within the coronary atherosclerotic plaque in 12 patients with various disease stages. In addition to macrophages, we find an abundance of plaque T cells that appear to be enriched in plaque compared to blood (Figure 1A). Two plaque-enriched CD8 effector memory clusters (CD8 CTL Tem1 and CD8 CTL Tem2) display the highest proportion of activated cells (e.g., HLA-DRA+). These clusters are characterized by high expression of the pro-inflammatory cytokines (e.g., CCL3, CCL4, CCL5, and IFNG) and cytolytic markers (e.g.,GZMA, GZMH, GZMM, NKG7). CD8 CTL Tem1, however, has higher expression of GZMK, a cytolytic marker recently associated with inflammaging. CD8 CTL Tem2, on the other hand, has a higher expression of perforin and granulysin, two pore-forming proteins that mediate cell killing by enabling granzyme entry. Notably, CD8 CTL Tem2 appears to track with plaque progression, increasing as plaques mature from lipid-rich to more complex lesions then declining as plaques became more stable and calcified post-rupture. Specifically, this cluster displayed two-fold enrichment in complex plaques compared to other plaque phenotypes (12.1% vs. 6.9%, p=0.0069) (Figure 1B). This pro-inflammatory and cytolytic signature is also more apparent in the activated compared to nonactivated cells in this cluster.Conclusion:Taken together, our findings suggest that a pro-inflammatory CD8 T cell cluster characterized by a trifecta of cytolytic enzymes distinguishes complex plaque and deserves further investigation.

A measurement system designed for the characterisation of chemorestive sensors based on novel materials is described. The system allows to simultaneously test up to eight sensors. It exploits an ad hoc structure based on an alumina substrate equipped with electrodes, a heater and an accurate temperature sensor, on which the material under study can be easily deposited by screen printing, spin coating or dip coating. The system is designed to study the behaviour of the sensors by accurately setting the working conditions in terms of chemical environment composition, gas flow, humidity and temperature. In particular the temperature of each sensor under test can be individually set by a digital control loop to a constant value or can be forced to follow an arbitrary time profile. The control system measures the sensing film temperature with a resolution close to 0.1°C and sets it with an uncertainty close to 1°C. Both chemical transients and thermal transients can be studied. These features make this system suitable for determining the principal performance indexes of a gas sensing device (e.g., sensitivity, stability, selectivity, response/recovery times, etc.) as functions of various combinations of measurement conditions (e.g., gas concentrations, temperature, humidity, flow).

Balkan Endemic Nephropathy (BEN) is a kidney degenerative disease with a high incidence in the valleys of the Danube and tributary rivers. Many studies describe it as a multifactorial disease. Environmental as well immuno-inflammatory and genetic cofactors have been suggested to trigger the onset of the disease. Recently, high levels of C-reactive protein were demonstrated in BEN patients. We performed this study to evaluate the possible correlation of BEN with the polymorphism of the Ig heavy chain 3'Regulatory Region enhancer hsl.2 that is related to changes of consensus for trans activators binding within the DNA sequence and probably consequently autoimmune and inflammatory diseases. Therefore, we studied three cohorts: 1) 111 control subjects, 2) 95 BEN patients in dialysis therapy and 3) 133 components of a large family “J” in the same geographical area. The allelic frequencies of hsl.2 of BEN patients and family “J” components had similar decrease frequency of allele *1 and increase of allele *2 in respect to the controls. This trend suggests the association of allele *1 as a protective and allele *2 as a risk component for the disease. The presence of a consensus sequence for NF-Kb in the allele *2 may link the polymorphism to the inflammatory activity of BEN. This study supports the presence of an inflammatory pathway in BEN through the involvement of polymorphic enhancer hsl.2 influencing differently binding complexes and consequently the 3D structure of 3' Regulatory Region of IgH. Our work is the first study that clearly links BEN to a gene involved in the regulation of immune response.

We developed an ex vivoapproach characterizing renal mesenchymal stem cell (MSC) adhesion to kidney sections. Specificity of MSC adhesion was confirmed by demonstrating a) 3T3 cells displayed 10-fold lower adhesion, and b) MSC adhesion was CXCR4/stromal-derived factor-1 (SDF-1)-dependent. MSC adhesion was asymmetrical, with postischemic sections exhibiting more than twofold higher adhesion than controls, and showed preference to perivascular areas. Pretreating kidney sections with cyclic arginine-glycine-aspartic acid peptide resulted in increased MSC adhesion (by displacing resident cells), whereas blockade of CXCR4 with AMD3100 and inhibition of α4β1(VLA4) integrin or vascular cellular adhesion molecule-1, reduced adhesion. The difference between adhered cells under cyclic arginine-glycine-aspartic acid peptide-treated and control conditions reflected prior occupancy of binding sites with endogenous cells. The AMD3100-inhibitable fraction of adhesion reflected CXCR4-dependent adhesion, whereas maximal adhesion was interpreted as kidney MSC-lodging capacity. MSC obtained from mice overexpressing caveolin-1 exhibited more robust adhesion than those obtained from knockout animals, consistent with CXCR4 dimerization in caveolae. These data demonstrate a) CXCR4/SDF-1-dependent adhesion increases in ischemia; b) CXCR4/SDF-1 activation is dependent on MSC surface caveolin-1; and c) occupancy of MSC binding sites is decreased, while d) capacity of MSC binding sites is expanded in postischemic kidneys. In conclusion, we developed a cell-bait strategy to unmask renal stem cell binding sites, which may potentially shed light on the MSC niche(s) and its characteristics.

Background: Acute kidney injury (AKI) following cardiac surgery with cardiopulmonary bypass (CPB) causes increased morbidity and mortality.Objective: To evaluate the plasma profile of biomarkers potentially involved in AKI development following CPB.Methods: In a nested case–control study, plasma levels of 27 biomarkers in 11 AKI cases were compared with 25 controls.Results: Pre-CPB, plasma levels of epidermal growth factor and macrophage inflammatory protein-1β, 2 h following CPB, soluble vascular cell adhesion molecule-1 (sVCAM-1), fractalkine and macrophage inflammatory protein-1α, and at later time points, sVCAM-1 and interleukin-6 were associated with AKI.Conclusion: Biomarkers associated with AKI following CPB may merit further study.

Primary and/or secondary injury of the renal microvascular endothelium is a common finding in various renal diseases. Besides well-known endothelial repair mechanisms, including endothelial cell (EC) proliferation and migration, homing of extrinsic cells such as endothelial progenitor cells (EPC) and hematopoietic stem cells (HSC) has been shown in various organs and may contribute to microvascular repair. However, these mechanisms have so far not been studied after selective microvascular injury in the kidney. The present study investigated the time course of EPC and HSC stimulation and homing following induction of selective EC injury in the mouse kidney along with various angiogenic factors potentially involved in EC repair and progenitor cell stimulation. Erythropoietin was used to stimulate progenitor cells in a therapeutic approach. We found that selective EC injury leads to a marked stimulation of EPCs, HSCs, and various angiogenic factors to orchestrate microvascular repair. Angiogenic factors started to increase as early as 30 min after disease induction. Progenitor cells could be first detected in the circulation and the spleen before they selectively homed to the diseased kidney. Injection of a high dose of erythropoietin 2 h after disease induction markedly attenuated vascular injury through nonhemodynamic mechanisms, possibly involving vascular endothelial growth factor release.

Adriamycin-associated nephropathy (AAN) remains poorly understood. We hypothesized that adriamycin affects endothelial progenitor cells (EPCs), leading to impaired regeneration. We analyzed renal hematopoietic stem cells (HSCs) and EPCs in mice with AAN and examined the potential contribution of adoptive transfer of intact EPCs to the repair processes. FACS analyses revealed that populations of HSCs and EPCs were scarcely represented in control kidneys and did not change numerically in kidneys obtained from mice with AAN. The observed defect in engraftment was attributable to the decreased viability and increased senescence of EPCs. Adoptive transfer of intact EPCs improved proteinuria and renal function, with a threefold decrease in mortality. Infusion of EPCs to adriamycin-treated mice reduced plasma levels of interleukin-1α and -β and granulocyte-colony stimulating factor as well as increased the level of vascular endothelial growth factor with concomitant improvement of vascular density and reduction of apoptosis. An additional mechanism of tissue repair is proposed based on tunneling nanotube formation between EPCs and endothelial cells exposed to adriamycin, leading to the multiple rounds of exchange between EPCs and mature cells. In conclusion, AAN is associated with development of EPC incompetence; adoptive transfer of intact EPCs blunts morphological and functional manifestations of AAN; and the proposed mechanisms of repair by EPCs include direct incorporation into blood vessels, paracrine signaling, and tunneling nanotube renewal of mitochondrial pool in endothelial cells.