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This present review systematically summarizes inherently secure and bioactive Zn involved nanomedicines for antineoplastic applications, presenting a promising development orientation for malignant tumor theranostics in the future.

Germline stem cells (GSCs) are critical for the reproduction of an organism. The self-renewal and differentiation of GSCs must be tightly controlled to avoid uncontrolled stem cell proliferation or premature stem cell differentiation. However, how the self-renewal and differentiation of GSCs are properly controlled is not fully understood. Here, we find that the novel intrinsic factor Yun is required for female GSC maintenance in Drosophila. GSCs undergo precocious differentiation due to de-repression of differentiation factor Bam by defective BMP/Dpp signaling in the absence of yun. Mechanistically, Yun associates with and stabilizes Thickveins (Tkv), the type I receptor of Dpp/BMP signaling. Finally, ectopic expression of a constitutively active Tkv (Tkv

During tumorigenesis, tumor cells interact intimately with their surrounding cells (microenvironment) for their growth and progression. However, the roles of tumor microenvironment in tumor development and progression are not fully understood. Here, using an established benign tumor model in adult Drosophila intestines, we find that non-cell autonomous autophagy (NAA) is induced in tumor surrounding neighbor cells. Tumor growth can be significantly suppressed by genetic ablation of autophagy induction in tumor neighboring cells, indicating that tumor neighboring cells act as tumor microenvironment to promote tumor growth. Autophagy in tumor neighboring cells is induced downstream of elevated ROS and activated JNK signaling in tumor cells. Interestingly, we find that active transport of nutrients, such as amino acids, from tumor neighboring cells sustains tumor growth, and increasing nutrient availability could significantly restore tumor growth. Together, these data demonstrate that tumor cells take advantage of their surrounding normal neighbor cells as nutrient sources through NAA to meet their high metabolic demand for growth and progression. Thus we provide insights into our understanding of the mechanisms underlying the interaction between tumor cells and their microenvironment in tumor development.

The fuel cell grid-tied power generation system usually includes a dc-dc converter and a dc-ac inverter. In a single-phase system, inherent low-order current pulsations are introduced into the system, which can have harmful effects on the fuel cell stack. For example, reducing the output voltage and output efficiency, a reduction in service life, and even accelerates the degradation rate of the membrane electrode of a proton exchange membrane fuel cell (PEMFC). In addition, dc/ac coupling power can cause distortion in the dc input current and ac grid current. To eliminate the input ripple and ensure high ac power quality on the grid side, this paper proposes a novel power decoupling control for single-phase grid-tied PEMFC systems, which uses an improved model predictive control (MPC) algorithm. With the help of the virtual vector methods, which are realized by a two-stage optimization method, excellent tracking effect and robustness can be ensured. Simulations and experimental results show that the proposed algorithm can not only completely eliminate the input current ripple and reduce the total harmonic distortion (THD) of ac current on the grid side, but also improve the transient performance of the system.

Purpose: We aimed to explore the prognostic value of integrin-β superfamily members (ITGBs) and their role in immune cell infiltration in non-small cell lung cancer (NSCLC). Materials and Methods: Study cases were acquired from The Cancer Genome Atlas database and The Human Protein Atlas. We then used R package and several online tools to analyze and visualize the roles of ITGBs in lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Results: We found that ITGBs were differentially expressed in NSCLC. In LUAD, high expression of ITGB1 and ITGB4 was an independent risk factor for poor prognosis, and ITGB7 was an independent protective factor for overall survival; in LUSC, high expression of ITGB1, 3, 5, and 6 was associated with poor prognosis, and ITGB8 was an independent protective factor for disease-specific survival. Protein-protein interaction networks for the most associated co-expressed genes revealed the following target genes of ITGBs: PTPRC, ITGAM, and ITGB2 in LUAD and FN1, PTPRC, and ITGB2 in LUSC. Gene ontology analysis revealed that functions related to adhesion, junction, and binding were highly enriched in LUAD and LUSC. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes in LUAD and LUSC. Conclusion: ITGBs were differentially expressed in NSCLC. ITGB1, 4, and 7 and ITGB1, 3, 5, 6, and 8 were found as prognostic markers in LUAD and LUSC, respectively. ITGBs were significantly associated with immune cell infiltration and the expression of immunomodulation-related genes.

Ultrasound-based haptic feedback is a potential technology for human–computer interaction (HCI) with the advantages of a low cost, low power consumption and a controlled force. In this paper, phase optimization for multipoint haptic feedback based on an ultrasound array was investigated, and the corresponding experimental verification is provided. A mathematical model of acoustic pressure was established for the ultrasound array, and then a phase-optimization model for an ultrasound transducer was constructed. We propose a pseudo-inverse (PINV) algorithm to accurately determine the phase contribution of each transducer in the ultrasound array. By controlling the phase difference of the ultrasound array, the multipoint focusing forces were formed, leading to various shapes such as geometries and letters, which can be visualized. Because the unconstrained PINV solution results in unequal amplitudes for each transducer, a weighted amplitude iterative optimization was deployed to further optimize the phase solution, by which the uniform amplitude distributions of each transducer were obtained. For the purpose of experimental verification, a platform of ultrasound haptic feedback consisting of a Field Programmable Gate Array (FPGA), an electrical circuit and an ultrasound transducer array was prototyped. The haptic performances of a single point, multiple points and dynamic trajectory were verified by controlling the ultrasound force exerted on the liquid surface. The experimental results demonstrate that the proposed phase-optimization model and theoretical results are effective and feasible, and the acoustic pressure distribution is consistent with the simulation results.

Stem cells maintain adult tissue homeostasis under physiological conditions. Uncontrolled stem cell proliferation will lead to tumorigenesis. How stem cell proliferation is precisely controlled is still not fully understood. Phosphorylation of Yun is essential for ISC proliferation. Yun is essential for the proliferation of normal and transformed intestinal stem cells. Our mass spectrometry and biochemical data suggest that Yun can be phosphorylated at multiple residues in vivo. Interestingly, we show that the phosphorylation among these residues is likely interdependent. Furthermore, phosphorylation of each residue in Yun is important for its function in ISC proliferation regulation. Thus, our study unveils the important role of post-translational modification of Yun in stem cell proliferation.

Significance Stem cells maintain tissue homeostasis. We identified a factor, Yun, required for proliferation of normal and transformed intestinal stem cells in adult Drosophila . Yun acts as a scaffold to stabilize the Prohibitin (PHB) complex previously implicated in various cellular and developmental processes and diseases. The Yun/PHB complex acts downstream of EGFR/MAPK signaling and affects the levels of E2F1 to regulate intestinal stem cell proliferation. The role of the PHB complex in cell proliferation is evolutionarily conserved. Our results provide insight into the underlying mechanisms of how stem cell proliferation is properly controlled during tissue homeostasis and tumorigenesis.

Disruption of tissue homeostasis often results in many diseases. Balanced control of stem cell proliferation and differentiation underlines tissue homeostasis. However, how endogenous factors influence the proliferation and differentiation of intestinal stem cells (ISCs) under physiological conditions remains not fully understood. Here, we find that the endoplasmic reticulum membrane protein complex (EMC) negatively regulates ISC proliferation in adultDrosophilamidgut. Compromising EMC function in progenitors leads to excessive ISC proliferation and intestinal homeostasis disruption. Mechanistically, the EMC complex associates with and stabilizes Hippo (Hpo), the key component of the Hpo signaling pathway. In the absence of the EMC complex, Yki (Yorkie) is activated to promote ISC proliferation. Furthermore, the role of the EMC complex in stem cell proliferation control is evolutionarily conserved. Thus, our study uncovers the molecular mechanism of the EMC complex in controlling stem cell proliferation. Our results provide new insight into the underlying mechanisms of how stem cell proliferation is properly controlled under physiological conditions.

The file contains all the original WB images

Stem cells constantly divide and differentiate to maintain adult tissue homeostasis, and uncontrolled stem cell proliferation leads to severe diseases such as cancer. How stem cell proliferation is precisely controlled remains poorly understood. Here, from an RNA interference (RNAi) screen in adult

Tissue phenotypic plasticity facilitates rapid adaptation of organisms to biotic and/or abiotic pressure. The reproductive capacity of honey bee workers (Apis mellifera) is plastic and responsive to pheromones produced by broods and the queen. Egg laying workers (ELWs), which could reactivate their ovaries and lay haploid eggs upon queen lost, have been commonly discussed from many aspects. However, it remains unclear whether midgut homeostasis in ELWs is affected during plastic changes. Here, we found that the expression of nutrition- and autophagy-related genes was up-regulated in the midguts of ELWs, compared with that in nurse workers (NWs) by RNA-sequencing. Furthermore, the area and number of autophagosomes were increased, along with significantly increased cell death in the midguts of ELWs. Moreover, cell cycle progression in the midguts of ELWs was increased compared with that in NWs. Consistent with the up-regulation of nutrition-related genes, the body and midgut sizes, and the number of intestinal proliferation cells of larvae reared with royal jelly (RJ) obviously increased more than those reared without RJ in vitro. Finally, cell proliferation was dramatically suppressed in the midguts of ELWs when autophagy was inhibited. Altogether, our data suggested that autophagy was induced and required to sustain cell proliferation in ELWs’ midguts, thereby revealing the critical role of autophagy played in the intestines during phenotypic plasticity changes.

Adult stem cells are critical for the maintenance of tissue homeostasis. However, how the proliferation and differentiation of intestinal stem cells (ISCs) are regulated remains not fully understood. Here, we find a mutant, stum 9-3, affecting the proliferation and differentiation of Drosophila adult ISCs in a forward genetic screen for factors regulating the proliferation and differentiation ISCs. stum 9-3 acts through the conserved Notch signaling pathway, upstream of the S2 cleavage of the Notch receptor. Interestingly, the phenotype of stum 9-3 mutant is not caused by disruption of stumble (stum), where the p-element is inserted. Detailed mapping, rescue experiments and mutant characterization show that stum 9-3 is a new allele of O-fucosyltransferase 1 (O-fut1). Our results indicate that unexpected mutants with interesting phenotype could be recovered in forward genetic screens using known p-element insertion stocks., Summary: A mutant, stum 9-3, affecting the proliferation and differentiation of Drosophila adult intestinal stem cells (ISCs) was identified in a forward genetic screen for factors regulating the proliferation and differentiation ISCs. stum 9-3 acts through the Notch signaling pathway. Detailed mapping, rescue experiments and characterization show that stum 9-3 is not a stumble mutant where the p-element is inserted, but a new allele of O-fucosyltransferase 1 (O-fut1).

Tissue homeostasis is controlled by the differentiated progeny of residential progenitors (stem cells). Adult stem cells constantly adjust their proliferation/differentiation rates to respond to tissue damage and stresses. However, how differentiated cells maintain tissue homeostasis remains unclear. Here, we find that heparan sulfate (HS), a class of glycosaminoglycan (GAG) chains, protects differentiated cells from loss to maintain intestinal homeostasis. HS depletion in enterocytes (ECs) leads to intestinal homeostasis disruption, with accumulation of intestinal stem cell (ISC)-like cells and mis-differentiated progeny. HS-deficient ECs are prone to cell death/stress and induced cytokine and epidermal growth factor (EGF) expression, which, in turn, promote ISC proliferation and differentiation. Interestingly, HS depletion in ECs results in the inactivation of decapentaplegic (Dpp) signaling. Moreover, ectopic Dpp signaling completely rescued the defects caused by HS depletion. Together, our data demonstrate that HS is required for Dpp signal activation in ECs, thereby protecting ECs from ablation to maintain midgut homeostasis. Our data shed light into the regulatory mechanisms of how differentiated cells contribute to tissue homeostasis maintenance.

Adult stem cells are critical for the maintenance of residential tissue homeostasis and functions. However, the roles of cellular protein homeostasis maintenance in stem cell proliferation and tissue homeostasis are not fully understood. Here, we find that Derlin-1 and TER94/VCP/p97, components of the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway, restrain intestinal stem cell proliferation to maintain intestinal homeostasis in adult Drosophila. Depleting any of them results in increased stem cell proliferation and midgut homeostasis disruption. Derlin-1 is specifically localized in the ER of progenitors, and its C-terminus is required for its function. Interestingly, we find that increased stem cell proliferation is resulted from elevated ROS levels and activated JNK signaling in Derlin-1- or TER94-deficient progenitors. Further removal of reactive oxygen species (ROS) or inhibition of JNK signaling almost completely suppresses increased stem cell proliferation. Together, these data demonstrate that the ERAD pathway is critical for stem cell proliferation and tissue homeostasis. Thus, we provide insights into our understanding of the mechanisms underlying cellular protein homeostasis maintenance (ER protein quality control) in tissue homeostasis and tumor development.

Adult tissue homeostasis is maintained by residential stem cells. The proliferation and differentiation of adult stem cells must be tightly balanced to avoid excessive proliferation or premature differentiation. However, how stem cell proliferation is properly controlled remains elusive. Here, we find that auxilin (Aux) restricts intestinal stem cell (ISC) proliferation mainly through EGFR signaling. aux depletion leads to excessive ISC proliferation and midgut homeostasis disruption, which is unlikely caused by defective Notch signaling. Aux is expressed in multiple types of intestinal cells. Interestingly, aux depletion causes a dramatic increase in EGFR signaling, with a strong accumulation of EGFR at the plasma membrane and an increased expression of EGFR ligands in response to tissue stress. Furthermore, Aux co-localizes and associates with EGFR. Finally, blocking EGFR signaling completely suppresses the defects caused by aux depletion. Together, these data demonstrate that Aux mainly safeguards EGFR activation to keep a proper ISC proliferation rate to maintain midgut homeostasis.

In this study, we report the identification and functional characterization of the Drosophila ben/ubc13 gene, encoding a unique ubiquitin-conjugating enzyme (Ubc or E2), in DNA-damage response. Ben forms a heterodimer with DmUev1a, the only Ubc/E2 variant (Uev) in Drosophila. Ben and DmUev1a act together to catalyze K63-linked polyubiquitination in vitro. ben can functionally rescue the yeast ubc13 null mutant from killing by DNA-damaging agents. We also find that BenP97S, which was previously described to affect the connectivity between the giant fiber and the tergotrochanter motor neuron, fails to interact with the RING protein Chfr but retains interaction with DmUev1a as well as Uevs from other species. The corresponding yeast Ubc13P97S interacts with Mms2 but fails to bind Rad5. Consequently, neither benP97S nor ubc13P97S is able to complement the yeast ubc13 mutant defective in error-free DNA-damage tolerance. More importantly, the benP97S mutant flies are more sensitive to a DNA-damaging agent, suggesting that Ben functions in a manner similar to its yeast and mammalian counterparts. Collectively, our observations imply that Ben-DmUev1a-promoted K63-linked polyubiquitination and involvement in DNA-damage response are highly conserved in eukaryotes including flies.

Stem cells have the potential to maintain the undifferentiated state and differentiate into specialized cell types. Despite numerous progresses have been achieved in understanding stem cell self-renewal and differentiation, many fundamental questions remain unanswered. In this study, we identify dRTEL1, the Drosophila homolog of Regulator of Telomere Elongation Helicase 1, as a novel regulator of Drosophila germline stem cells (GSCs). Our genome-wide transcriptome analysis and ChIP-Seq results suggest that dRTEL1 directly regulates a set of candidate genes controlling GSC self-renewal and differentiation. Furthermore, dRTEL1 prevents DNA damage-induced checkpoint activation for GSC maintenance. Finally, dRTEL1 is required to maintain Stat92E protein levels, the key player in GSC self-renewal. Together, our findings reveal an intrinsic role of the DNA helicase dRTEL1 in GSC self-renewal and provide insight into the function of dRTEL1.

Stem cell competition could select the fittest stem cells and potentially control tumorigenesis. However, little is known about the underlying molecular mechanisms. Here, we find that ectopic Decapentaplegic (Dpp) signal activation by expressing a constitutively active form of Thickveins (TkvCA) in cyst stem cells (CySCs) leads to competition between CySCs and germline stem cells (GSCs) for niche occupancy and GSC loss. GSCs are displaced from the niche and undergo differentiation. Interestingly, we find that induction of TkvCA results in elevated expression of vein, which further activates Epidermal Growth Factor Receptor (EGFR) signaling in CySCs to promote their proliferation and compete GSCs out of the niche. Our findings elucidate the important role of Dpp signaling in regulating stem cell competition and tumorigenesis, which could be shed light on tumorigenesis and cancer treatment in mammals.

K63-linked polyubiquitination requires the ubiquitin-conjugating enzyme Ubc13 and a Ubc/E2 variant Uev. Lower eukaryotic organisms contain one UEV gene required for DNA-damage tolerance, while vertebrates and higher plants contain multiple UEV genes with distinct functions. In contrast, Drosophila contains only one UEV gene designated dUev1a. Here we report that dUev1a forms a stable heterodimer with Ben, the Drosophila Ubc13 ortholog, that dUev1a-F15E completely abolishes the interaction, and that a conserved dUev1a-F15Y substitution severely reduces its interaction with Ben. dUev1a functionally rescues the corresponding yeast mms2 null mutant from killing by various DNA-damaging agents in a Ben-dependent manner, and the heterozygous dUev1a mutant flies are more sensitive to DNA-damaging agent, indicating that the function of UEV in DNA-damage response is conserved throughout eukaryotes. Meanwhile, dUev1a+/- mutant flies displayed reduced mobility characteristic of defects in the central nervous system and reminiscent of the bendless phenotypes, suggesting that dUev1a acts together with Ben in this process. Our observations collectively imply that dUev1a is dually required for DNA-damage response and neurological signaling in Drosophila, and that these processes are mediated by the Ben-dUev1a complex that promotes K63-linked polyubiquitination.

Adult tissue homeostasis is maintained by residential stem cells through the proper balance of stem cell self-renewal and differentiation. The adult midgut of Drosophila contains multipotent intestinal stem cells (ISCs), and Notch signaling plays critical roles in the proliferation and differentiation of these ISCs. However, how Notch signaling downstream targets regulate ISC proliferation and differentiation still remains unclear. Here we find that Notch signaling downstream targets E(spl)mbeta and E(spl)malpha are differentially expressed in ISCs and their progeny. Interestingly, we find that midgut homeostasis is not affected in E(spl)mbeta null mutant. No obvious defects are observed in the intestines ectopically expressing E(spl)mbeta or E(spl)malpha. Importantly, we find that the defects in ISC proliferation and differentiation observed in Notch mutant cannot be rescued by ectopic expression of E(spl)mbeta or E(spl)malpha. Together, these data indicate that the proliferation and differentiation of ISCs are not regulated by individual Notch downstream target, but by different downstream targets collectively.

Most, if not all, stem cells reside in a defined microenvironment, called the niche. Short-ranged niche signal must be tightly controlled to be active only inside the niche to maintain the proper balance of stem cell self-renewal verse differentiation. However, how niche components restrict localized niche signal activation remains largely unknown. Here, we find that Thickveins (Tkv, a type I receptor of the Dpp signaling pathway) in cyst stem cells (CySCs) of the testis niche prevents Dpp signaling activation outside of the niche. We show that Tkv functions as Dpp trap/sink to spatially restrain Dpp signaling inside the niche. This self-restrained regulation of niche activity by Tkv in CySCs is independent of the canonical Dpp signaling pathway. Our data demonstrate the critical roles of niche components (CySCs) in the self-restrained regulation of niche activity, which could be shed light on niche activity regulation in general.

Tissue homeostasis is maintained by differentiated progeny of residential stem cells. Adult stem cells constantly adjust their proliferation and differentiation rate to respond to tissue damage and stresses. However, how differentiated cells maintain tissue homeostasis still remains unclear. Here, we find that heparan sulfate (HS), a class of glycosaminoglycan (GAG) chains, protects differentiated cells to maintain intestinal homeostasis. HS depletion in enterocytes (ECs) leads to midgut homeostasis disruption, with accumulation of intestinal stem cell (ISC)-like cells and their progeny. HS-deficient ECs are prone to cell death/stress and induced the expression of cytokines and epidermal growth factors (EGFs), which in turn promote ISC proliferation and differentiation. Interestingly, HS depletion in ECs results in inactivation of Decapentaplegic (Dpp) signaling. Moreover, ectopic Dpp signaling completely rescued the defects caused by HS depletion. Taken together, these data demonstrate that HS protects ECs from ablation by Dpp signaling activation to maintain midgut homeostasis. Our results provide insight into the regulatory mechanisms of how differentiated cells contributes to tissue homeostasis control.

The proliferation and differentiation of adult stem cells must be tightly controlled in order to maintain resident tissue homeostasis. Dysfunction of stem cells is implicated in many human diseases, including cancer. However, the regulation of stem cell proliferation and differentiation is not fully understood. Here we show that the sterile-like 20 kinase, Tao, controls tissue homeostasis by regulating the Hippo pathway in the Drosophila adult midgut. Depletion of Tao in the progenitors leads to rapid intestinal stem cell (ISC) proliferation and midgut homeostasis loss. Meanwhile, we find that the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling activity and cytokine production are significantly increased, resulting in stimulated ISC proliferation. Furthermore, expression of the Hippo pathway downstream targets, Diap1 and bantam, is dramatically increased in Tao knockdown intestines. Consistently, we show that the Yorkie (Yki) acts downstream of Tao to regulate ISC proliferation. Together, our results provide insights into our understanding of the mechanisms of stem cell proliferation and tissue homeostasis control.

SummaryHomeostasis in adult tissues is maintained by resident stem cells and their progeny. Little is known about the regulation of tissue homeostasis by organ-organ interaction. Here we demonstrate that trachea-derived Decapentaplegic (Dpp), the main bone morphogenetic protein ligand in Drosophila, is essential for adult midgut homeostasis. We show that Dpp signaling is primarily activated in enterocytes (ECs). Depletion of Dpp signaling in ECs results in excess amounts of intestinal stem-cell-like cells and their progeny. Importantly, we find that Dpp is expressed specifically in tracheal cells that reach the intestinal cells through the visceral muscles. Depletion of dpp expression in tracheal cells phenocopies the Dpp loss-of-function defects in ECs. Our data demonstrate that the Drosophila trachea not only exchanges air for bodily needs but also produces a Dpp morphogen essential for neighboring tissue homeostasis. This work will provide important insights into the mechanisms of tissue homeostasis control by interorgan communication.

The stem cell niche, formed by surrounding stromal cells, provides extrinsic signals that maintain stem cell self-renewal. However, it remains unclear how these extrinsic signals are regulated. In the Drosophila female germline stem cell (GSC) niche, Decapentaplegic (DPP) is an important niche factor for GSC self-renewal. The exact source of the DPP and how its transcription is regulated in this niche remain unclear. We show that dpp is expressed in somatic cells of the niche including the cap cells, a subtype of niche cells. Furthermore, our data show that the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway positively regulates dpp expression in the cap cells, suggesting that JAK/STAT activity is required in somatic niche cells to prevent precocious GSC differentiation. Our data suggest that the JAK/STAT pathway functions downstream/independently of cap cell formation induced by Notch signaling. JAK/STAT signaling may also regulate dpp expression in the male GSC niche, suggesting a common origin of female and male GSC niches.

Asymmetrical localization of transcripts coupled with localized translation constitutes an important mechanism widely deployed to regulate gene activity in a spatial manner. The conserved transmembrane protein Crumbs (Crb) is an important regulator of epithelial polarity. However, it remains unclear how Crb is targeted to the apical domain. Here, we show that the cytoplasmic dynein complex transports both Crb protein and transcripts to the apical domain of Drosophila melanogaster follicular cells (FCs). The crb 3′ untranslated region (UTR) is necessary and sufficient for the apical localization of its transcript and this apical transcript localization is crucial for crb function. In crb mutant FCs, Crb protein derived from transgenes lacking the 3′ UTR does not effectively localize to the apical domain and does not effectively restore normal epithelial polarity. We propose that dynein-mediated messenger RNA transport coupled with a localized translation mechanism is involved in localizing Crb to the apical domain to mediate epithelial apicobasal polarity and that this mechanism might be widely used to regulate cellular polarity.

Adult stem cells or residential progenitor cells are critical to maintain the structure and function of adult tissues (homeostasis) throughout the lifetime of an individual. Mis-regulation of stem cell proliferation and differentiation often leads to diseases including cancer, however, how wildtype adult stem cells and cancer cells respond to cellular damages remains unclear. We find that in the adult Drosophila midgut, intestinal stem cells (ISCs), unlike tumor intestinal cells, are resistant to various cellular damages. Tumor intestinal cells, unlike wildtype ISCs, are easily eliminated by apoptosis. Further, their proliferation is inhibited upon autophagy induction, and autophagy-mediated tumor inhibition is independent of cas-pase-dependent apoptosis. Interestingly, inhibition of tumorigenesis by autophagy is likely through the sequestration and degradation of mitochondria, as compromising mitochondria activity in these tumor models mimics the induction of autophagy and increasing the production of mitochondria alleviates the tumor-suppression capacity of autophagy. Together, these data demonstrate that wildtype adult stem cells and tumor cells show dramatic differences in sensitivity to cellular damages, thus providing potential therapeutic implications targeting tumorigenesis.

The adult intestinal homeostasis is tightly controlled by proper proliferation and differentiation of intestinal stem cells. The JAK/STAT (Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway is essential for the regulation of adult stem cell activities and maintenance of intestinal homeostasis. Currently, it remains largely unknown how JAK/STAT signaling activities are regulated in these processes. Here we have identified windpipe (wdp) as a novel component of the JAK/STAT pathway. We demonstrate that Wdp is positively regulated by JAK/STAT signaling in Drosophila adult intestines. Loss of wdp activity results in the disruption of midgut homeostasis under normal and regenerative conditions. Conversely, ectopic expression of Wdp inhibits JAK/STAT signaling activity. Importantly, we show that Wdp interacts with the receptor Domeless (Dome), and promotes its internalization for subsequent lysosomal degradation. Together, these data led us to propose that Wdp acts as a novel negative feedback regulator of the JAK/STAT pathway in regulating intestinal homeostasis., Author Summary Effective tissue homeostasis requires a proper balance between the removal of dead cells and production of new cells. Due to environmental challenges, the Drosophila midgut epithelial cells are damaged from time to time and intestinal stem cells (ISC) can accelerate their proliferative rate to replace the lost midgut epithelium. The JAK/STAT pathway plays essential roles in these progresses. Upon damage, Upd ligands produced by dying enterocytes (ECs) activate JAK/STAT signaling in ISCs to promote their proliferation and differentiation. However, after damage how JAK/STAT signaling is switched from a highly active state to a homeostatic state is not yet fully understood. In this study, we identified the leucine rich repeats (LRR) protein Windpipe (Wdp) as a novel negative feedback regulator of JAK/STAT signaling during intestinal development. Wdp expression was induced by high levels of JAK/STAT signaling in intestines. And loss of Wdp leads to midgut homeostasis loss and increased ISC proliferation. Furthermore, we found Wdp in turn negatively regulates JAK/STAT signaling activity through promoting Domeless receptor endocytosis and lysosomal degradation. In this way, high levels of JAK/STAT signaling is switched off by Wdp, which ensure ISCs return to the homeostatic state after tissue damage.

In the present work a modified Split Hopkinson Pressure Bar (SHPB) system is adopted to perform dynamic fiber push-out experiments on model single fiber composite systems. A tapered punch and a support connect a monofilament composite with the incident and transmitted bars of the SHPB. The tapered punch is used to apply compressive loading to a single fiber (either steel or aluminum) embedded in a surrounding matrix material (EPON 862). The SHPB allows real time measurement of relative fiber/matrix displacement and push-out force, as the debonding and push-out event progresses. Using this technique we have studied the effect of loading rate, material mismatch, fiber length, and surface roughness on the push-out event. It was seen that maximum push-out force increases with increasing loading rate. In addition dynamic interfacial strength and toughness is highly dependent on fiber surface roughness. Results from a finite element analysis incorporating a cohesive failure model were used to extract interface strength and toughness values. It was found that the particular aluminum/EPON interface used is characterized by a dynamic shear failure strength of 48±8 MPa, a mode II fracture toughness of 160±40 N/m, and a friction coefficient of 0.2 at a sliding rate of 6 m/s. For the rates tested here these quantities were found to be approximately constant.

This paper summarizes our recent progress on the experimental and numerical study of dynamic fiber debonding and frictional push-out in model composite systems. A modified split Hopkinson pressure bar system is adopted to perform dynamic fiber push-out experiments. A cohesive/volumetric finite element scheme is developed to capture the initiation and propagation of the crack along the fiber/matrix interface. Interface properties are extracted by comparison between experimental and numerical results. Details of the physical process are analyzed by investigating numerically the propagation and evolution of the axial stress along the entire system. The numerical method is applied to an aluminum/epoxy model composite system. Finally, effects of several important parameters such as interfacial strength, interfacial fracture toughness, fiber/matrix friction coefficient and loading rate are investigated.

The role of plastic deformation in generating heat during dynamic compression and fracture of polycarbonate was examined in a combined experimental and numerical investigation. Split Hopkinson pressure bar (SHPB) experiments and opening mode dynamic fracture experiments were performed to measure the thermomechanical response of polycarbonate at various loading conditions. A companion set of dynamic, thermomechanically coupled explicit finite element simulations of the tested geometries was performed to isolate the temperature increase of the polymer due to plasticity effects only, and these were then compared to the experiments to identify the role of plasticity in the overall heating of the polymer. Temperature measurements during the experiments were made with a remote sensing technique that utilizes the detection of infrared radiation. Polycarbonate was observed to have a rate dependent yield and plastic deformation response under uniaxial compression. For the strain rates tested in the SHPB experiments (400 to 3000 s−1), the fraction of plastic work rate converted to heat was found to be approximately 0.5. The dynamic fracture experiments indicated that the maximum temperature increase in the region surrounding the propagating crack was over 100 K, and the crack tip velocity was limited to approximately 60% of the Rayleigh wave speed. The numerical simulations used the plastic behavior of polycarbonate observed during the compression SHPB experiments as inputs for an incremental plasticity model that uses a rate dependent Mises yield surface and isotropic hardening. Plastic deformation was the only source of material heating in the simulations. Good agreement between the SHPB experiments and the numerical simulations was seen for both stress and temperature during the compression event. Crack growth during the dynamic fracture simulations was imposed by a manual node release technique that duplicated the crack growth speed observed in the experiments. The dynamic fracture simulations which only included the thermoplastic effect significantly under-predicted the temperature increase in the region surrounding the propagating crack. The results indicate that plastic deformation is not the dominating source of heat generation during the dynamic fracture of polycarbonate, it only accounts for about 8% of the measured heating. Additional effects, such as thermofracture coupling, must be considered in the simulations if a more accurate comparison is to be made with experiments.