AMIGO2 attenuates innate cisplatin sensitivity by suppression of GSDME-conferred pyroptosis in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) accounts for approximately 85% of lung cancer. Cisplatin is commonly used in the treatment of many malignant tumours including NSCLC. The innate drug sensitivity greatly affects the clinical efficacy of cisplatin-based chemotherapy. As a plasma membrane adhesion molecule, amphoterin-induced gene and ORF-2 (AMIGO2) initially identified as a neurite outgrowth factor has been recently found to play a crucial role in cancer occurrence and progression. However, it is still unclear whether AMIGO2 is involved in innate cisplatin sensitivity. In the present study, we provided the in vitro and in vivo evidences indicating that the alteration of AMIGO2 expression triggered changes of innate cisplatin sensitivity as well as cisplatin-induced pyroptosis in NSCLC. Further results revealed that AMIGO2 might inhibit cisplatin-induced activation of (caspase-8 and caspase-9)/caspase-3 via stimulating PDK1/Akt (T308) signalling axis, resulting in suppression of GSDME cleavage and the subsequent cell pyroptosis, thereby decreasing the sensitivity of NSCLC cells to cisplatin treatment. The results provided a new insight that AMIGO2 regulated the innate cisplatin sensitivity of NSCLC through GSDME-mediated pyroptosis.

Facile fabrication of ordered discontinuous nanotopography on photosensitive substrates for enhanced neuronal differentiation.

Controlling the development and morphology of neurons is important for basic neuroscience research as well as for applications in nerve regeneration and neural interfaces. Various studies have shown that nanoscale topographies can promote the development of neuronal cells and the differentiation of neural stem cells; however, the fabrication of these nanotopographical features often involves expensive and sophisticated techniques. Here, we employ nanosphere lens lithography combined with UV-LED technology to create nanopatterns on an SU-8 photoresist. We develop a facile method to create a reusable polystyrene nanosphere (PS-NS) lens array by the spontaneous formation of a hexagonal close-packed array of PS-NSs at a water-air interface and its subsequent transfer to a polydimethylsiloxane carrier film without using any special equipment. We show that this simple technique can create ordered arrays of nanodots on an SU-8 film, the dimensions of which can be controlled by the size of the PS-NSs. When used as a substrate for the neuronal differentiation of pheochromocytoma (PC12) cells, the nanopatterned SU-8 films exhibit enhanced differentiation parameters with respect to conventional tissue culture plastic as compared with their flat counterparts. The method proposed here can greatly facilitate the nanopatterning of various photosensitive substrates for the development of implants for nerve regeneration and neural interfacing.

Delayed grafting for banked skin graft in lymph node flap transfer.

Over the last decade, lymph node flap (LNF) transfer has turned out to be an effective method in the management of lymphoedema of extremities. Most of the time, the pockets created for LNF cannot be closed primarily and need to be resurfaced with split thickness skin grafts. Partial graft loss was frequently noted in these cases. The need to prevent graft loss on these iatrogenic wounds made us explore the possibility of attempting delayed skin grafting. We have herein reported our experience with delayed grafting with autologous banked split skin grafts in cases of LNF transfer for lymphoedema of the extremities. Ten patients with International Society of Lymphology stage II-III lymphoedema of upper or lower extremity were included in this study over an 8-month period. All patients were thoroughly evaluated and subjected to lymph node flap transfer. The split skin graft was harvested and banked at the donor site, avoiding immediate resurfacing over the flap. The same was carried out in an aseptic manner as a bedside procedure after confirming flap viability and allowing flap swelling to subside. Patients were followed up to evaluate long-term outcomes. Flap survival was 100%. Successful delayed skin grafting was done between the 4th and 6th post-operative day as a bedside procedure under local anaesthesia. The split thickness skin grafts (STSG) takes more than 97%. One patient needed additional medications during the bedside procedure. All patients had minimal post-operative pain and skin graft requirement. The patients were also reported to be satisfied with the final aesthetic results. There were no complications related to either the skin grafts or donor sites during the entire period of follow-up. Delayed split skin grafting is a reliable method of resurfacing lymph node flaps and has been shown to reduce the possibility of flap complications as well as the operative time and costs.

The combined transverse upper gracilis and profunda artery perforator (TUGPAP) flap for breast reconstruction.

BACKGROUND: Surgical options for breast reconstruction include alloplastic and autogenous reconstructions. In autologous cases where the abdomen is not a suitable primary donor site, secondary donor sites such as the thigh or buttock are considered. The aim of this report is to describe a novel approach, the combined transverse upper gracilis and profunda artery perforator (TUGPAP) flap, aimed at medium to large volume breast reconstruction, with a single donor site used per breast. METHODS: Between January 2011 and June 2013, 32 consecutive unilateral immediate breast reconstruction cases were performed using free flaps. In nine cases, patients had previously undergone abdominal surgery, therefore abdominal flaps were excluded and TUGPAP flaps were performed. The TUGPAP flap consisted of the combination of two well-described flaps: the transverse upper gracilis (TUG) and the profunda artery perforator (PAP) flap. All TUGPAP flaps were based on two pedicles: the ascending branch of the medial circumflex femoral artery (MCFA) for the TUG component, and the profunda artery perforator itself for the PAP component. RESULTS: The mean size of the harvested skin paddle was 28.6 × 8 cm2 (range, 27 × 7 cm2 to 30 × 9 cm2). The average length of the TUG flap pedicle was 7 cm (range, 6-8 cm) and the PAP flap pedicle was 9 cm (range, 8.5-10 cm). The flap survival rate was 100% with no re-exploration, and no partial flap loss. Post-operatively there was one case of persistent donor site seroma, which was managed conservatively. CONCLUSION: With appropriate patient selection and surgical technique the TUGPAP flap could be a valuable option as an alternative method for autologous breast reconstruction. © 2015 Wiley Periodicals, Inc. Microsurgery, 2015.

Clueless regulates aPKC activity and promotes self-renewal cell fate in Drosophila lgl mutant larval brains.

Asymmetric cell division of Drosophila neural stem cells or neuroblasts is an important process which gives rise to two different daughter cells, one of which is the stem cell itself and the other, a committed or differentiated daughter cell. During neuroblast asymmetric division, atypical Protein Kinase C (aPKC) activity is tightly regulated; aberrant levels of activity could result in tumorigenesis in third instar larval brain. We identified clueless (clu), a genetic interactor of parkin (park), as a novel regulator of aPKC activity. It preferentially binds to the aPKC/Bazooka/Partition Defective 6 complex and stabilizes aPKC levels. In clu mutants, Miranda (Mira) and Numb are mislocalized in small percentages of dividing neuroblasts. Adult mutants are short-lived with severe locomotion defects. Clu promotes tumorigenesis caused by loss of function of lethal(2) giant larvae (lgl) in the larval brain. Removal of clu in lgl mutants rescues Mira and Numb mislocalization and restores the enlarged brain size. Western blot analyses indicate that the rescue is due to the down-regulation of aPKC levels in the lgl clu double mutant. Interestingly, the phenotype of the park mutant, which causes Parkinson's Disease-like symptoms in adult flies, is reminiscent of that of clu in neuroblast asymmetric division. Our study provides the first clue for the potential missing pathological link between temporally separated neurogenesis and neurodegeneration events; the minor defects during early neurogenesis could be a susceptible factor contributing to neurodegenerative diseases at later stages of life.

Impedimetric monitoring of IGF-1 protection of in vitro cortical neurons under ischemic conditions.

Microelectrode arrays (MEAs) incorporated with the electric cell substrate impedance sensing (ECIS) technique provide a method for acquiring cellular electrophysiological information, which is useful for the time-course monitoring of cellular outgrowth and damage. This research utilizes the ECIS technique for monitoring the time-course impedimetric changes in normal and insulin-like growth factor 1 (IGF-1)-protected cortical neurons under the ischemic insult of oxygen glucose deprivation (OGD) created in a microperfusion environment. The neuronal apoptosis is reflected by the relatively low cell viability (28 ± 11.5 %) after 30-min OGD followed by 24 h of re-oxygenation. Also the hyperpolarization phase of mitochondrial membrane potential (MMP) occurs during 2 h of the re-oxygenation period. In contrast, cortical neurons treated with 50 and 100 ng/mL IGF-1 show higher survival rates of 45 ± 5.2 % and 49 ± 9.2 %, respectively, and no occurrence of the hyperpolarization of MMP during the re-oxygenation period. The ECIS results demonstrate that the measured impedance of cortical neurons decreased from 826 ± 86 kΩ to 224 ± 32 kΩ due to cell detachment under the insult of OGD. The measured impedance of IGF-1-protected cortical neurons slowly decreased to about 50 % of the original value (560 ± 45 kΩ for 50 ng/mL and 593 ± 44 kΩ for 100 ng/mL) compared to saline control of 232 ± 37 kΩ, which indicates improved cell adhesion under OGD conditions. The time-course impedimetric results show that the proposed ECIS-based MEAs platform incorporated with a microperfusion environment can be used for the real-time monitoring of cortical neurons under in vitro OGD and the IGF-1 protective effect against OGD-induced ischemic neuronal death.

Suppression and interpersonal harmony: a cross-cultural comparison between Chinese and European Americans.

Based on Markus and Kitayama's (1991) theory, this study was conducted to examine whether the association between emotional suppression and interpersonal harmony would be moderated by cultural group (i.e., Chinese and European Americans) and an Asian cultural value (i.e., emotional self-control). A total of 451 college students (205 Chinese and 246 European Americans) participated in this study. As expected, results indicated that the association between emotional suppression and interpersonal harmony was significantly positive for Chinese but not significant for European Americans. Similarly, when emotional self-control was examined as a moderator, the results still confirmed our hypotheses. That is, the association between emotional suppression and interpersonal harmony was significantly positive for those with stronger endorsement of emotional self-control but not for those with weaker endorsement of emotional self-control. Furthermore, we examined whether the above results could be replicated when forbearance (a construct similar to suppression) and distress disclosure (a construct opposite to suppression) were examined. The results showed the same pattern for forbearance and distress disclosure when cultural group or emotional self-control served as the moderator. The convergence of findings increased the robustness of our results. Finally, our data suggest that individuals from Eastern, interdependent cultures (e.g., Chinese) tend to value emotional suppression to preserve interpersonal harmony; individuals from Western, independent cultures may or may not necessarily suppress their emotions for this purpose. A comprehensive understanding of the different meanings of a specific strategy (i.e., emotional suppression) in different cultural contexts is important to promote effective cross-cultural counseling.

Hierarchically patterned polyurethane microgrooves featuring nanopillars or nanoholes for neurite elongation and alignment.

Surface micro- and nanostructures profoundly affect the functional performance of nerve regeneration implants by modulating neurite responses. However, few studies have investigated the impact of discrete nanostructures, such as nanopillars and nanoholes, and their combination with microgrooves on neurite outgrowth and alignment. Furthermore, numerous techniques have been developed for surface micro-/nanopatterning, but simple and low-cost approaches are quite limited. In this work, we show that nanopillars and nanoholes, and their combination with microgrooves, can be patterned on polyurethane (PU) films using a low-cost, reusable photoresist master mold prepared via nanosphere lens lithography and UV-LED photolithography, with specific "reinforcement" methods for overcoming the inherent drawbacks of using photoresist masters. We show that the PU nanopillars and nanoholes increase the neurite length of pheochromocytoma 12 (PC12) cells through unique growth cone interactions. Moreover, we demonstrate, for the first time, that hierarchically patterned nano-/microstructured PU films enhance both PC12 neurite elongation and alignment, showing the potential use of our proposed method for the micro-/nanopatterning of polymers for nerve tissue engineering.

Detection of lactate in human sweat via surface-modified, screen-printed carbon electrodes.

Real-time and continuous monitoring of lactate levels in sweat has been used as an indicator of physiological information to evaluate exercise outcomes and sports performance. We developed an optimal enzyme-based biosensor to detect the concentrations of lactate in different fluids (i.e., a buffer solution and human sweat). The surface of the screen-printed carbon electrode (SPCE) was first treated with oxygen plasma and then surface-modified by lactate dehydrogenase (LDH). The optimal sensing surface of the LDH-modified SPCE was identified by Fourier transform infrared spectroscopy and electron spectroscopy for chemical analysis. After connecting the LDH-modified SPCE to a benchtop E4980A precision LCR meter, our results showed that the measured response was dependent on the lactate concentration. The recorded data exhibited a broad dynamic range of 0.1-100 mM (R2 = 0.95) and a limit of detection of 0.1 mM, which was unachievable without the incorporation of redox species. A state-of-the-art electrochemical impedance spectroscopy (EIS) chip was developed to integrate the LDH-modified SPCE for a portable bioelectronic platform in the detection of lactate in human sweat. We believe the optimal sensing surface can improve the sensitivity of lactate sensing in a portable bioelectronic EIS platform for early diagnosis or real-time monitoring during different physical activities.

Nano-Brush Structure for Rapid Label-Free Differentiation of Alzheimer's Disease Stages and Direct Capture of Neuron-Derived Exosomes from Human Blood Plasma.

The measurement of the neurofilament light chain (NFL) in human blood plasma/serum is a promising liquid biopsy for Alzheimer's disease (AD) diagnosis, offering advantages over conventional neuroimaging techniques recommended in clinical guidelines. Here, a controllable nano-brush structure comprising upstanding silicon nanowires coated with indium tin oxide was employed as the sensing substrate. This nano-brush structure was modified with an NFL antibody (NFLAb) via silane coupling and then further connected as the extended gate in a field-effect transistor (EGFET). Notable signal differences emerged within a 2 min timeframe, enabling the label-free differentiation in human blood plasmas among four distinct cohorts: healthy controls, subjective cognitive decline, mild cognitive impairment, and dementia due to AD. Our study indicates that achieving a surface roughness exceeding 400 nm on the modified nano-brush structure enables the effective electrical sensing in our EGFETs. These distinct electrical responses measured via the NFLAb-modified nano-brush EGFETs can be attributed to the combined effects of the captured NFLs and NFL-specific neuron-derived exosomes (NDEs) found in dementia patients, as confirmed by electron spectroscopy for chemical analysis, atomic force microscopy, and scanning electron microscopy. Finally, the potential of quantitatively detecting NDEs on the NFLAb-modified nano-brush structure was demonstrated using spiked solutions containing NFL-specific NDEs from IMR-32 neuroblast cells, wherein concentration-dependent changes were observed in the EGFETs output signal. Our findings show that the NFLAb-modified nano-brush EGFET enables rapid, label-free differentiation between healthy individuals and patients at varying stages of AD.

A Multimodality Electrochemical and Impedance Spectroscopy System-on-a-Chip With Temperature Sensing and Impedance-Boosting Techniques.

This article presents a multimodal electrochemical sensing system-on-chip (SoC), including the functions of cyclic voltammetry (CV), electrochemical impedance spectroscopy (EIS), and temperature sensing. CV readout circuitry achieves an adaptive readout current range of 145.5 dB through an automatic range adjustment and resolution scaling technique. EIS has an impedance resolution of 9.2 m Ω/√ Hz at a sweep frequency of 10 kHz and an output current of up to 120 µA. With an impedance boost mechanism, the maximum detectable load impedance is extended to 22.95 k Ω, while the total harmonic distortion is less than 1%. A resistor-based temperature sensor using a swing-boosted relaxation oscillator can achieve a resolution of 31 mK in 0-85 °C. The design is implemented in a 0.18 µm CMOS process. The total power consumption is 1 mW.

Advisory working alliance, perceived English proficiency, and acculturative stress.

The aim of this study was to examine the moderators of (a) general or cross-cultural advisory working alliances and (b) perceived English proficiency on the association between acculturative stress and psychological distress. A total of 143 East Asian international students completed an online survey. Results from a hierarchical regression indicated significant three-way interactions of (a) General Advisory Working Alliances × Perceived English Proficiency × Acculturative Stress on Psychological Distress and (b) Cross-Cultural Advisory Working Alliances × Perceived English Proficiency × Acculturative Stress on Psychological Distress. Specifically, the present results indicated that acculturative stress was significantly associated with psychological distress only when students perceived lower English proficiency and had a stronger general or cross-cultural advisory working alliance. However, acculturative stress was not significantly related to psychological distress when these students perceived lower English proficiency and had a weaker advisory working alliance (i.e., general or cross-cultural). In addition, acculturative stress was also not significantly related to psychological distress when these students perceived higher English proficiency and had a stronger or weaker advisory working alliance (i.e., general or cross-cultural).

Investigation into the effect of varied functional biointerfaces on silicon nanowire MOSFETs.

A biocompatible and functional interface can improve the sensitivity of bioelectronics. Here, 3-aminopropyl trimethoxysilane (APTMS) and 3-mercaptopropyl trimethoxysilane (MPTMS) self-assembled monolayers (SAMs) were independently modified on the surface of silicon nanowire metal-oxide-semiconductor field effect transistors (NW-MOSFETs). Those SAMs-modified silicon NW-MOSFETs were used to discriminate various pH solutions and further verify which modified regime was capable of providing better electrical signals. The APTMS-SAM modified NW-MOSFETs showed better electrical responses in pH sensing. Biomolecules on APTMS-SAM modified NW-MOSFETs also gave better signals for the corresponding proteind in physiological buffer solutions. Atomic force microscopy (AFM) clarified those electrical phenomena and found biomolecules on APTMS-SAM were relatively uniformly modified on NW-MOSFETs. Our results showed that more uniform modification contributed to better signal response to protein interactions in physiological buffer solutions. It suggests that suitable surface modifications could profoundly affect the sensing response and sensitivity.

Ionic Hydrogel for Efficient and Scalable Moisture-Electric Generation.

The progress of spontaneous energy generation from ubiquitous moisture is hindered the low output current and intermittent operating voltage of the moisture-electric generators. Herein a novel and efficient ionic hydrogel moisture-electric generator (IHMEG) is developed by rational combination of poly(vinyl alcohol), phytic acid, and glycerol-water binary solvent. Thanks to the synergistic effect of notable moisture-absorption capability and fast ion transport capability in the ionic hydrogel network, a single IHMEG unit of 0.25 cm2 can continuously generate direct-current electricity with a constant open-circuit voltage of ≈0.8 V for over 1000 h, a high short-current density of 0.24 mA cm-2 , and power density of up to 35 µW cm-2 . Of great importance is that large-scale integration of IHMEG units can be readily accomplished to offer a device with voltage up to 210 V, capable of directly driving numerous commercial electronics, including electronic ink screen, metal electrodeposition setup, and light-emitting-diode arrays. Such prominent performance is mainly attributed to the enhanced moisture-liberated proton diffusion proved by experimental observation and theoretical analysis. The ionic hydrogel with high cost-efficiency, easy-to-scaleup fabrication, and high power-output opens a brand-new perspective to develop a green, versatile, and efficient power source for Internet-of-Things and wearable electronics.

Wireless Multimodality Sensing System-on-a-Chip With Time-Based Resolution Scaling Technique and Analog Waveform Generator in 0.18 µm CMOS for Chronic Wound Care.

Multimodal sensing can provide a comprehensive and accurate diagnosis of biological information. This paper presents a fully integrated wireless multimodal sensing chip with voltammetric electrochemical sensing at a scanning rate range of 0.08-400 V/s, temperature monitoring, and bi-phasic electrical stimulation for wound healing progress monitoring. The time-based readout circuitry can achieve a 1-20X scalable resolution through dynamic threshold voltage adjustment. A low-noise analog waveform generator is designed using current reducer techniques to eliminate the large passive components. The chip is fabricated via a 0.18 µm CMOS process. The design achieves R2 linearity of 0.995 over a wide current detection range (2 pA-12 µA) while consuming 49 µW at 1.2 V supply. The temperature sensing circuit achieves a 43 mK resolution from 20 to 80 degrees. The current stimulator provides an output current ranging from 8 µA to 1 mA in an impedance range of up to 3 kΩ. A wakeup receiver with data correlators is used to control the operation modes. The sensing data are wirelessly transmitted to the external readers. The proposed sensing IC is verified for measuring critical biomarkers, including C-reactive protein, uric acid, and temperature.

High-content image generation for drug discovery using generative adversarial networks.

Immense amount of high-content image data generated in drug discovery screening requires computationally driven automated analysis. Emergence of advanced machine learning algorithms, like deep learning models, has transformed the interpretation and analysis of imaging data. However, deep learning methods generally require large number of high-quality data samples, which could be limited during preclinical investigations. To address this issue, we propose a generative modeling based computational framework to synthesize images, which can be used for phenotypic profiling of perturbations induced by drug compounds. We investigated the use of three variants of Generative Adversarial Network (GAN) in our framework, viz., a basic Vanilla GAN, Deep Convolutional GAN (DCGAN) and Progressive GAN (ProGAN), and found DCGAN to be most efficient in generating realistic synthetic images. A pre-trained convolutional neural network (CNN) was used to extract features of both real and synthetic images, followed by a classification model trained on real and synthetic images. The quality of synthesized images was evaluated by comparing their feature distributions with that of real images. The DCGAN-based framework was applied to high-content image data from a drug screen to synthesize high-quality cellular images, which were used to augment the real image data. The augmented dataset was shown to yield better classification performance compared with that obtained using only real images. We also demonstrated the application of proposed method on the generation of bacterial images and computed feature distributions for bacterial images specific to different drug treatments. In summary, our results showed that the proposed DCGAN-based framework can be utilized to generate realistic synthetic high-content images, thus enabling the study of drug-induced effects on cells and bacteria.

A Two-Electrode, Double-Pulsed Sensor Readout Circuit for Cardiac Troponin I Measurement.

This paper presents a pulse-stimulus sensor readout circuit for use in cardiovascular disease examinations. The sensor is based on a gold nanoparticle plate with an antibody post-modification. The proposed system utilizes gated pulses to detect the biomarker Cardiac Troponin I in an ionic solution. The characteristic of the electrostatic double-layer capacitor generated by the analyte is related to the concentration of Cardiac Troponin I in the solvent. After sensing by the transistor, a current-to-frequency converter (I-to-F) and delay-line-based time-to-digital converter (TDC) convert the information into a series of digital codes for further analysis. The design is fabricated in a 0.18-µm standard CMOS process. The chip occupies an area of 0.92 mm2 and consumes 125 µW. In the measurements, the proposed circuit achieved a 1.77 Hz/pg-mL sensitivity and 72.43 dB dynamic range.

Identification of PP2A and S6 Kinase as Modifiers of Leucine-Rich Repeat Kinase-Induced Neurotoxicity.

Mutations in LRRK2 are currently recognized as the most common monogenetic cause of Parkinsonism. The elevation of kinase activity of LRRK2 that frequently accompanies its mutations is widely thought to contribute to its toxicity. Accordingly, many groups have developed LRRK2-specific kinase inhibitors as a potential therapeutic strategy. Given that protein phosphorylation is a reversible event, we sought to elucidate the phosphatase(s) that can reverse LRRK2-mediated phosphorylation, with the view that targeting this phosphatase(s) may similarly be beneficial. Using an unbiased RNAi phosphatase screen conducted in a Drosophila LRRK2 model, we identified PP2A as a genetic modulator of LRRK2-induced neurotoxicity. Further, we also identified ribosomal S6 kinase (S6K), a target of PP2A, as a novel regulator of LRRK2 function. Finally, we showed that modulation of PP2A or S6K activities ameliorates LRRK2-associated disease phenotype in Drosophila.

pS421 huntingtin modulates mitochondrial phenotypes and confers neuroprotection in an HD hiPSC model.

Huntington disease (HD) is a hereditary neurodegenerative disorder caused by mutant huntingtin (mHTT). Phosphorylation at serine-421 (pS421) of mHTT has been shown to be neuroprotective in cellular and rodent models. However, the genetic context of these models differs from that of HD patients. Here we employed human pluripotent stem cells (hiPSCs), which express endogenous full-length mHTT. Using genome editing, we generated isogenic hiPSC lines in which the S421 site in mHTT has been mutated into a phospho-mimetic aspartic acid (S421D) or phospho-resistant alanine (S421A). We observed that S421D, rather than S421A, confers neuroprotection in hiPSC-derived neural cells. Although we observed no effect of S421D on mHTT clearance or axonal transport, two aspects previously reported to be impacted by phosphorylation of mHTT at S421, our analysis revealed modulation of several aspects of mitochondrial form and function. These include mitochondrial surface area, volume, and counts, as well as improved mitochondrial membrane potential and oxidative phosphorylation. Our study validates the protective role of pS421 on mHTT and highlights a facet of the relationship between mHTT and mitochondrial changes in the context of human physiology with potential relevance to the pathogenesis of HD.

Delay QoS and MAC Aware Energy-Efficient Data-Aggregation Routing in Wireless Sensor Networks.

By eliminating redundant data flows, data aggregation capabilities in wireless sensor networks could transmit less data to reduce the total energy consumption. However, additional data collisions incur extra data retransmissions. These data retransmissions not only increase the system energy consumption, but also increase link transmission delays. The decision of when and where to aggregate data depends on the trade-off between data aggregation and data retransmission. The challenges of this problem need to address the routing (layer 3) and the MAC layer retransmissions (layer 2) at the same time to identify energy-efficient data-aggregation routing assignments, and in the meantime to meet the delay QoS. In this paper, for the first time, we study this cross-layer design problem by using optimization-based heuristics. We first model this problem as a non-convex mathematical programming problem where the objective is to minimize the total energy consumption subject to the data aggregation tree and the delay QoS constraints. The objective function includes the energy in the transmission mode (data transmissions and data retransmissions) and the energy in the idle mode (to wait for data from downstream nodes in the data aggregation tree). The proposed solution approach is based on Lagrangean relaxation in conjunction with a number of optimization-based heuristics. From the computational experiments, it is shown that the proposed algorithm outperforms existing heuristics that do not take MAC layer retransmissions and the energy consumption in the idle mode into account.