Is There Such a Thing as a Biosignature?

The concept of a biosignature is widely used in astrobiology to suggest a link between some observation and a biological cause, given some context. The term itself has been defined and used in several ways in different parts of the scientific community involved in the search for past or present life on Earth and beyond. With the ongoing acceleration in the search for life in distant time and/or deep space, there is a need for clarity and accuracy in the formulation and reporting of claims. Here, we critically review the biosignature concept(s) and the associated nomenclature in light of several problems and ambiguities emphasized by recent works. One worry is that these terms and concepts may imply greater certainty than is usually justified by a rational interpretation of the data. A related worry is that terms such as "biosignature" may be inherently misleading, for example, because the divide between life and non-life-and their observable effects-is fuzzy. Another worry is that different parts of the multidisciplinary community may use non-equivalent or conflicting definitions and conceptions, leading to avoidable confusion. This review leads us to identify a number of pitfalls and to suggest how they can be circumvented. In general, we conclude that astrobiologists should exercise particular caution in deciding whether and how to use the concept of biosignature when thinking and communicating about habitability or life. Concepts and terms should be selected carefully and defined explicitly where appropriate. This would improve clarity and accuracy in the formulation of claims and subsequent technical and public communication about some of the most profound and important questions in science and society. With this objective in mind, we provide a checklist of questions that scientists and other interested parties should ask when assessing any reported detection of a "biosignature" to better understand exactly what is being claimed.

Directional Aspects of Vegetation Linear and Circular Polarization Biosignatures.

Homochirality is a generic and unique property of all biochemical life and it is considered a universal and agnostic biosignature. Upon interaction with unpolarized light, homochirality induces fractional circular polarization in the light that is scattered from it, which can be sensed remotely. As such, it can be a prime candidate biosignature in the context of future life detection missions and observatories. The linear polarizance of vegetation is also sometimes envisaged as a biosignature, although it does not share the same molecular origin as circular polarization. It is known that linear polarization of surfaces is strongly dependent on the phase angle. The relationship between the phase angle and circular polarization stemming from macromolecular assemblies such as in vegetation, however, remained unclear. In this study, using the average of 27 different species, we demonstrate that the circular polarization-phase angle dependency of vegetation induces relatively small changes in spectral shape and mostly affects the signal magnitude. With these results, we underline the use of circular spectropolarimetry as a promising agnostic biosignature complementary to the use of linear spectropolarimetry and scalar reflectance.

Determinants of Domestic Risk Prevention Behavior: The Importance of Separating Effects Within-Persons and Between-Persons.

The effects of vulnerability, severity, costs, effort, and effectiveness on prevention behavior, derived from protection motivation theory and the health belief model, have been extensively tested in the literature and have all been shown to predict rather well. In this study we test the effects of these determinants in a new context: the domestic risk prevention domain. The specific behaviors under study are related to the risks of burglary, fire, and water damage. In addition to previous studies, our multilevel research design allows us to evaluate which differences in the performance of domestic prevention behavior can be attributed to differences between persons and which to differences between behaviors within persons. Our results show that all determinants are relevant predictors for domestic risk prevention behavior. Disentangling the within-person and between-person effects shows that prevention behavior depends more on the relative evaluation of the prevention behavior determinants for a given person (e.g., a person perceives a smoke alarm to be more effective than antiburglar strips), than on the differences between persons regarding the general perception of these determinants (e.g., some persons find prevention behaviors in general more effective than other persons). To increase the performance of domestic risk prevention behaviors, we advise that interventions should focus on increasing a person's perception of risks and prevention behaviors relative to other risks and prevention behaviors rather than focusing on changing people's general perceptions of all risks and behaviors or focusing on specific target groups.

Playing with fire. Understanding how experiencing a fire in an immersive virtual environment affects prevention behavior.

A potentially effective way to influence people's fire prevention behavior is letting them experience a fire in an immersive virtual environment (IVE). We analyze the effects of experiencing a fire in an IVE (versus an information sheet) on psychological determinants of behavior-knowledge, vulnerability, severity, self-efficacy, and locus of control-based mainly on arguments from Protection Motivation Theory and the Health Belief Model. Crucial in our setup is that we also relate these determinants to actual prevention behavior. Results show that IVE has the hypothesized effects on vulnerability, severity, and self-efficacy, and an unexpected negative effect on knowledge. Only knowledge and vulnerability showed subsequent indirect effects on actual prevention behavior. There remains a direct positive effect of IVE on prevention behavior that cannot be explained by any of the determinants. Our results contradict the implicit assumption that an induced change in these psychological determinants by IVE, necessarily implies a change in behavior. A recommendation for research on the effects of IVE's is, whenever possible, to study the actual target behavior as well.

Circular Spectropolarimetric Sensing of Vegetation in the Field: Possibilities for the Remote Detection of Extraterrestrial Life.

Homochirality is a generic and unique property of all biochemical life, and the fractional circular polarization of light it induces therefore constitutes a potentially unambiguous biosignature. However, while high-quality circular polarimetric spectra can be easily and quickly obtained in the laboratory, accurate measurements in the field are much more challenging due to large changes in illumination and target movement. In this study, we measured various targets in the field, up to distances of a few kilometers, using the dedicated circular spectropolarimeter TreePol. We show how photosynthetic life can readily be distinguished from abiotic matter. We underline the potential of circular polarization signals as a remotely accessible means to characterize and monitor terrestrial vegetation, for example, for agriculture and forestry. In addition, we discuss the potential of circular polarization for the remote detection of extraterrestrial life.

Circular spectropolarimetric sensing of higher plant and algal chloroplast structural variations.

Photosynthetic eukaryotes show a remarkable variability in photosynthesis, including large differences in light-harvesting proteins and pigment composition. In vivo circular spectropolarimetry enables us to probe the molecular architecture of photosynthesis in a non-invasive and non-destructive way and, as such, can offer a wealth of physiological and structural information. In the present study, we have measured the circular polarizance of several multicellular green, red, and brown algae and higher plants, which show large variations in circular spectropolarimetric signals with differences in both spectral shape and magnitude. Many of the algae display spectral characteristics not previously reported, indicating a larger variation in molecular organization than previously assumed. As the strengths of these signals vary by three orders of magnitude, these results also have important implications in terms of detectability for the use of circular polarization as a signature of life.

Imaging linear and circular polarization features in leaves with complete Mueller matrix polarimetry.

Spectropolarimetry of intact plant leaves allows to probe the molecular architecture of vegetation photosynthesis in a non-invasive and non-destructive way and, as such, can offer a wealth of physiological information. In addition to the molecular signals due to the photosynthetic machinery, the cell structure and its arrangement within a leaf can create and modify polarization signals. Using Mueller matrix polarimetry with rotating retarder modulation, we have visualized spatial variations in polarization in transmission around the chlorophyll a absorbance band from 650 nm to 710 nm. We show linear and circular polarization measurements of maple leaves and cultivated maize leaves and discuss the corresponding Mueller matrices and the Mueller matrix decompositions, which show distinct features in diattenuation, polarizance, retardance and depolarization. Importantly, while normal leaf tissue shows a typical split signal with both a negative and a positive peak in the induced fractional circular polarization and circular dichroism, the signals close to the veins only display a negative band. The results are similar to the negative band as reported earlier for single macrodomains. We discuss the possible role of the chloroplast orientation around the veins as a cause of this phenomenon. Systematic artefacts are ruled out as three independent measurements by different instruments gave similar results. These results provide better insight into circular polarization measurements on whole leaves and options for vegetation remote sensing using circular polarization.

Frequent Versus Infrequent Monitoring of Endotracheal Tube Cuff Pressures.

BACKGROUND: Currently there is no accepted standard of practice for the optimal frequency of endotracheal tube cuff pressure monitoring in mechanically ventilated patients. Therefore, we conducted a study to compare infrequent endotracheal tube cuff pressure monitoring (immediately after intubation and when clinically indicated for an observed air leak or due to tube migration) with frequent endotracheal tube cuff pressure monitoring (immediately after intubation, every 8 h, and when clinically indicated). METHODS: We performed a prospective clinical trial with subjects assigned to study groups based on room assignment. The primary outcome was the occurrence of a ventilator-associated event (VAE) and was adjudicated by individuals blinded to the conduct of this study. RESULTS: We enrolled 305 subjects, with 166 (54.4%) assigned to frequent monitoring and 139 (45.6%) assigned to infrequent monitoring. The total number of endotracheal tube cuff pressure monitoring events for both groups was 1,531 versus 336, respectively. The occurrence of VAEs was infrequent and similar for both groups (3.6% vs 5.8%, P = .37). Witnessed aspiration events (0.6% vs 0%, P = .36), ventilator-associated pneumonia (0% vs 0.7%, P = .27), 30-d mortality (31.3% vs 30.2%, P = .83), and hospital length of stay (10 d [6 d, 21 d] vs 11 d [6 d, 21 d], P = .34) were also similar for both study groups. The 30-d hospital readmission rate was statistically lower for the group that received infrequent monitoring (15.1% vs 6.5%, P = .02). CONCLUSIONS: More frequent cuff pressure monitoring was not associated with any identifiable clinical outcome benefit.

A Respiratory Therapist Disease Management Program for Subjects Hospitalized With COPD.

BACKGROUND: Patients with COPD often require repeated emergency department visits and hospitalizations for COPD exacerbations. Such readmissions increase health-care costs and expose COPD patients to the added risks of nosocomial infections and increased mortality. METHODS: To determine whether a respiratory therapist (RT) disease management program could reduce re-hospitalization and emergency department visits, a prospective, single-center, unblinded, randomized trial was performed. RESULTS: We enrolled 428 subjects (214 intervention, 214 control). The primary outcome (combined non-hospitalized emergency department visits and hospital readmissions for a COPD exacerbation during the 6-month follow-up) was similar for the study groups (91 vs 159, P = .08). When the 2 components of the primary end point were analyzed individually, the percentage of subjects with non-hospitalized emergency department visits for COPD exacerbations was similar between groups (15.0% vs 15.9%, P = .79). Readmission for a COPD exacerbation was significantly lower in the intervention group (20.1% vs 28.5%, P = .042). The median (interquartile range) duration of hospitalization for a COPD exacerbation was less for the intervention group (5 [3-11] d vs 8 [4-18.5] d, P = .045). In-patient hospital days (306 d vs 523 d, P = .02) and ICU days (17 d vs 53 d, P = .02) due to COPD exacerbations were significantly less for the intervention group. Mortality was similar for both groups (1.4% vs 0.9%, P > .99). CONCLUSIONS: Our RT disease management program was associated with less readmission, fewer ICU days, and shorter hospital stays due to COPD exacerbations. Further studies are needed to determine the optimal utilization of RT disease management teams for patients with COPD to optimize outcomes and prevent return hospital visits. (ClinicalTrials.gov registration NCT01543217.).

Melatonin Signal Transduction Pathways Require E-Box-Mediated Transcription of Per1 and Per2 to Reset the SCN Clock at Dusk.

Melatonin is released from the pineal gland into the circulatory system at night in the absence of light, acting as "hormone of darkness" to the brain and body. Melatonin also can regulate circadian phasing of the suprachiasmatic nucleus (SCN). During the day-to-night transition, melatonin exposure advances intrinsic SCN neural activity rhythms via the melatonin type-2 (MT2) receptor and downstream activation of protein kinase C (PKC). The effects of melatonin on SCN phasing have not been linked to daily changes in the expression of core genes that constitute the molecular framework of the circadian clock. Using real-time RT-PCR, we found that melatonin induces an increase in the expression of two clock genes, Period 1 (Per1) and Period 2 (Per2). This effect occurs at CT 10, when melatonin advances SCN phase, but not at CT 6, when it does not. Using anti-sense oligodeoxynucleotides (α ODNs) to Per 1 and Per 2, as well as to E-box enhancer sequences in the promoters of these genes, we show that their specific induction is necessary for the phase-altering effects of melatonin on SCN neural activity rhythms in the rat. These effects of melatonin on Per1 and Per2 were mediated by PKC. This is unlike day-active non-photic signals that reset the SCN clock by non-PCK signal transduction mechanisms and by decreasing Per1 expression. Rather, this finding extends roles for Per1 and Per2, which are critical to photic phase-resetting, to a nonphotic zeitgeber, melatonin, and suggest that the regulation of these clock gene transcripts is required for clock resetting by diverse regulatory cues.

Use of a Shared Canister Protocol for the Delivery of Metered-Dose Inhalers in Mechanically Ventilated Subjects.

BACKGROUND: Mechanically ventilated patients often need bronchodilators administered via a metered-dose inhaler (MDI). Unfortunately, there are no data examining the impact of shared canister delivery of MDI therapy in mechanically ventilated patients. METHODS: A prospective trial was conducted with subjects assigned to shared canister MDI therapy or single-patient canister MDI therapy. Outcomes assessed were occurrence of ventilator-associated pneumonia (VAP), hospital mortality, length of stay, ventilator-associated events, and MDI costs. RESULTS: Among 486 screened patients, 353 were included for analysis of which 201 (56.9%) received shared canister MDI therapy and 152 (43.1%) received single-patient canister therapy. VAP (7.0% vs 4.6%, P = .35), hospital mortality (21.9% vs 20.4%, P = .73), and ventilator days (median [interquartile range] 3.1 [0.9-7.5] d vs 2.7 [1.2-7.1] d, P = .62) were similar between the shared canister and single-patient canister groups. We did not observe clinically important differences for ventilator-associated events between study groups in our logistic regression analysis (P = .07). There was a savings of $217/subject in the shared canister group due to the use of 299 fewer MDIs. CONCLUSIONS: Our study found that shared canister MDI therapy compared with single-patient MDI use was associated with a significant cost savings and similar rates of VAP, hospital mortality, and length of stay but a greater prevalence of ventilator-associated events. This finding suggests that shared canister delivery of MDIs may be a cost-effective practice in mechanically ventilated patients. Based on our findings, further studies examining the overall safety of shared canister use in mechanically ventilated patients seem warranted before recommending their routine use. (ClinicalTrials.gov registration NCT01935388.).

Presynaptic dystrophic neurites surrounding amyloid plaques are sites of microtubule disruption, BACE1 elevation, and increased Aß generation in Alzheimer's disease.

Alzheimer's disease (AD) is characterized by amyloid plaques composed of the ß-amyloid (Aß) peptide surrounded by swollen presynaptic dystrophic neurites consisting of dysfunctional axons and terminals that accumulate the ß-site amyloid precursor protein (APP) cleaving enzyme (BACE1) required for Aß generation. The cellular and molecular mechanisms that govern presynaptic dystrophic neurite formation are unclear, and elucidating these processes may lead to novel AD therapeutic strategies. Previous studies suggest Aß may disrupt microtubules, which we hypothesize have a critical role in the development of presynaptic dystrophies. To investigate this further, here we have assessed the effects of Aß, particularly neurotoxic Aß42, on microtubules during the formation of presynaptic dystrophic neurites in vitro and in vivo. Live-cell imaging of primary neurons revealed that exposure to Aß42 oligomers caused varicose and beaded neurites with extensive microtubule disruption, and inhibited anterograde and retrograde trafficking. In brain sections from AD patients and the 5XFAD transgenic mouse model of amyloid pathology, dystrophic neurite halos with BACE1 elevation around amyloid plaques exhibited aberrant tubulin accumulations or voids. At the ultrastructural level, peri-plaque dystrophies were strikingly devoid of microtubules and replete with multi-lamellar vesicles resembling autophagic intermediates. Proteins of the microtubule motors, kinesin and dynein, and other neuronal proteins were aberrantly localized in peri-plaque dystrophies. Inactive pro-cathepsin D also accumulated in peri-plaque dystrophies, indicating reduced lysosomal function. Most importantly, BACE1 accumulation in peri-plaque dystrophies caused increased BACE1 cleavage of APP and Aß generation. Our study supports the hypothesis that Aß induces microtubule disruption in presynaptic dystrophic neurites that surround plaques, thus impairing axonal transport and leading to accumulation of BACE1 and exacerbation of amyloid pathology in AD.

Randomized, placebo-controlled trials of dichlorphenamide in periodic paralysis.

OBJECTIVE: To determine the short-term and long-term effects of dichlorphenamide (DCP) on attack frequency and quality of life in hyperkalemic (HYP) and hypokalemic (HOP) periodic paralysis. METHODS: Two multicenter randomized, double-blind, placebo-controlled trials lasted 9 weeks (Class I evidence), followed by a 1-year extension phase in which all participants received DCP. Forty-four HOP and 21 HYP participants participated. The primary outcome variable was the average number of attacks per week over the final 8 weeks of the double-blind phase. RESULTS: The median attack rate was lower in HOP participants on DCP than in participants on placebo (0.3 vs 2.4, p = 0.02). The 9-week mean change in the Physical Component Summary score of the Short Form-36 was also better in HOP participants receiving DCP (treatment effect = 7.29 points, 95% confidence interval 2.26 to 12.32, p = 0.006). The median attack rate was also lower in HYP participants on DCP (0.9 vs 4.8) than in participants on placebo, but the difference in median attack rate was not significant (p = 0.10). There were no significant effects of DCP on muscle strength or muscle mass in either trial. The most common adverse events in both trials were paresthesia (47% DCP vs 14% placebo, both trials combined) and confusion (19% DCP vs 7% placebo, both trials combined). CONCLUSIONS: DCP is effective in reducing the attack frequency, is safe, and improves quality of life in HOP periodic paralysis. CLASSIFICATION OF EVIDENCE: These studies provide Class I evidence that DCP significantly reduces attack frequency in HOP but lacked the precision to support either efficacy or lack of efficacy of DCP in HYP.

Reactive transport modeling of subsurface arsenic removal systems in rural Bangladesh.

Subsurface Arsenic Removal (SAR) is a technique for in-situ removal of arsenic from groundwater. Extracted groundwater is aerated and re-injected into an anoxic aquifer, where the oxygen in the injected water reacts with ferrous iron in the aquifer to form hydrous ferric oxide (HFO). Subsequent extraction of groundwater contains temporarily lower As concentrations, because As sorbs onto the HFO. Injection, storage, and extraction together is called a cycle. A reactive transport model (RTM) was developed in PHREEQC to determine the hydrogeochemical processes responsible for As (im)mobilization during experimental SAR operation performed in Bangladesh. Oxidation of Fe(II) and As(III) were modeled using kinetic-rate expressions. Cation exchange, precipitation of HFO, and surface complexation, were modeled as equilibrium processes. A best set of surface complexation reactions and corresponding equilibrium constants was adopted from previous studies to simulate all 20 cycles of a SAR experiment. The model gives a reasonable match with observed concentrations of different elements in the extracted water (e.g., the r(2) value of As was 0.59 or higher). As concentrations in the extracted water are governed by four major processes. First, As concentration decreases in response to the elevated pH of injection water and likewise increases when native neutral pH groundwater flows in. Second, the sorption capacity for As increases due to the gradual buildup of HFO. Third, As sorption is enhanced by preferential removal of As(V). Fourth, competitive sorption of Si limits the capacity of freshly precipitated HFO for As sorption. Transferability of the developed reactive transport model was demonstrated through successful application of the model, without further calibration, to two additional SAR sites in Bangladesh. This gives confidence that the model could be useful to assess potential SAR performance at locations in Bangladesh based on local hydrogeochemical conditions.

The Significance of Microbe-Mineral-Biomarker Interactions in the Detection of Life on Mars and Beyond.

The detection of biomarkers plays a central role in our effort to establish whether there is, or was, life beyond Earth. In this review, we address the importance of considering mineralogy in relation to the selection of locations and biomarker detection methodologies with characteristics most promising for exploration. We review relevant mineral-biomarker and mineral-microbe interactions. The local mineralogy on a particular planet reflects its past and current environmental conditions and allows a habitability assessment by comparison with life under extreme conditions on Earth. The type of mineral significantly influences the potential abundances and types of biomarkers and microorganisms containing these biomarkers. The strong adsorptive power of some minerals aids in the preservation of biomarkers and may have been important in the origin of life. On the other hand, this strong adsorption as well as oxidizing properties of minerals can interfere with efficient extraction and detection of biomarkers. Differences in mechanisms of adsorption and in properties of minerals and biomarkers suggest that it will be difficult to design a single extraction procedure for a wide range of biomarkers. While on Mars samples can be used for direct detection of biomarkers such as nucleic acids, amino acids, and lipids, on other planetary bodies remote spectrometric detection of biosignatures has to be relied upon. The interpretation of spectral signatures of photosynthesis can also be affected by local mineralogy. We identify current gaps in our knowledge and indicate how they may be filled to improve the chances of detecting biomarkers on Mars and beyond.

Elevated TAK1 augments tumor growth and metastatic capacities of ovarian cancer cells through activation of NF-κB signaling.

Transforming growth factor (TGF)-ß-activating kinase 1 (TAK1) is a serine/threonine kinase which is frequently associated with human cancer progression. However, its functional role in tumorigenesis is still controversial. Here, we report that TAK1 enhances the oncogenic capacity of ovarian cancer cells through the activation of NF-κB signaling. We found that TAK1 is frequently upregulated and significantly associated with high-grade and metastatic ovarian cancers. Mechanistic studies showed that Ser412 phosphorylation is required for TAK1 in activating NF-κB signaling and promotes aggressiveness of ovarian cancer cells. Conversely, suppression of TAK1 activity by point mutation at Ser412, RNAi mediated gene knockdown or TAK1 specific inhibitor ((5Z) -7-Oxozeaenol) remarkably impairs tumor growth and metastasis in ovarian cancer in vitro and in vivo. Our study underscores the importance of targeting TAK1 as a promising therapeutic approach to counteract the ovarian cancer progression.

The normal and pathologic roles of the Alzheimer's ß-secretase, BACE1.

As the most common neurodegenerative disease, therapeutic avenues for the treatment and prevention of Alzheimer's Disease are highly sought after. The aspartic protease BACE1 is the initiator enzyme for the formation of Aß, a major constituent of amyloid plaques that represent one of the hallmark pathological features of this disorder. Thus, targeting BACE1 for disease-modifying AD therapies represents a rationale approach. The collective knowledge acquired from investigations of BACE1 deletion mutants and characterization of BACE1 substrates has downstream significance not only for the discovery of AD drug therapies but also for predicting side effects of BACE1 inhibition. Here we discuss the identification and validation of BACE1 as the ß-secretase implicated in AD, in addition to information regarding BACE1 cell biology, localization, substrates and potential physiological functions derived from BACE1 knockout models.

The Alzheimer's ß-secretase BACE1 localizes to normal presynaptic terminals and to dystrophic presynaptic terminals surrounding amyloid plaques.

ß-Site amyloid precursor protein (APP) cleaving enzyme-1 (BACE1) is the ß-secretase that initiates Aß production in Alzheimer's disease (AD). BACE1 levels are increased in AD, which could contribute to pathogenesis, yet the mechanism of BACE1 elevation is unclear. Furthermore, the normal function of BACE1 is poorly understood. We localized BACE1 in the brain at both the light and electron microscopic levels to gain insight into normal and pathophysiologic roles of BACE1 in health and AD, respectively. Our findings provide the first ultrastructural evidence that BACE1 localizes to vesicles (likely endosomes) in normal hippocampal mossy fiber terminals of both non-transgenic and APP transgenic (5XFAD) mouse brains. In some instances, BACE1-positive vesicles were located near active zones, implying a function for BACE1 at the synapse. In addition, BACE1 accumulated in swollen dystrophic autophagosome-poor presynaptic terminals surrounding amyloid plaques in 5XFAD cortex and hippocampus. Importantly, accumulations of BACE1 and APP co-localized in presynaptic dystrophies, implying increased BACE1 processing of APP in peri-plaque regions. In primary cortical neuron cultures, treatment with the lysosomal protease inhibitor leupeptin caused BACE1 levels to increase; however, exposure of neurons to the autophagy inducer trehalose did not reduce BACE1 levels. This suggests that BACE1 is degraded by lysosomes but not by autophagy. Our results imply that BACE1 elevation in AD could be linked to decreased lysosomal degradation of BACE1 within dystrophic presynaptic terminals. Elevated BACE1 and APP levels in plaque-associated presynaptic dystrophies could increase local peri-plaque Aß generation and accelerate amyloid plaque growth in AD.

AMPK activators suppress cervical cancer cell growth through inhibition of DVL3 mediated Wnt/ß-catenin signaling activity.

Recent evidence has suggested that AMPK activators may be applied as therapeutic drugs in suppressing cancer cell growth. However, the molecular mechanism of their suppressive function in cancer cells is still unclear. Here we show that AMPK activators impair cervical cancer cell growth through the reduction of DVL3, a positive regulator in Wnt/ß-catenin signaling and an oncogenic player in cervical cancer tumorigenesis. By western blot and immunohistochemical analyses, we demonstrated that DVL3 was frequently upregulated and significantly associated with elevated ß-catenin (P = 0.009) and CyclinD1 (P = 0.009) expressions in cervical cancer. Enforced expression of DVL3 elevated ß-catenin and augmented cervical cancer cell growth, verifying that DVL3-mediated Wnt/ß-catenin activation is involved in cervical cancer oncogenesis. On the other aspect, we noted that the cervical cancer cell growth was remarkably suppressed by AMPK activators and such cell growth inhibition was in concomitant with the reduction of DVL3 protein level in dose- and time-dependent manners. Besides, impaired mTOR signaling activity also reduced DVL3 expression. In contrast, co-treatment with Compound C (AMPK inhibitor) could significantly abrogate metformin induced DVL3 reduction. In addition, co-treatment with AM114 or MG132 (proteosomal inhibitors) could partially restore DVL3 expression under the treatment of metformin. Further in vivo ubiquitination assay revealed that metformin could reduce DVL3 by ubiquitin/proteasomal degradation. To our knowledge, this is the first report showing the probable molecular mechanisms of that the AMPK activators suppress cervical cancer cell growth by impairing DVL3 protein synthesis via AMPK/mTOR signaling and/or partially promoting the proteasomal degradation of DVL3.

Current status of adult spinal deformity.

Purpose To review the current literature for the nonoperative and operative treatment for adult spinal deformity. Recent Findings With more than 11 million baby boomers joining the population of over 60 years of age in the United States, the incidence of lumbar deformity is greatly increasing. Recent literature suggests that a lack of evidence exists to support the effectiveness of nonoperative treatment for adult scoliosis. In regards to operative treatment, current literature reports a varying range of improved clinical outcomes, curve correction, and complication rates. The extension of fusion to S1 compared with L5 and lower thoracic levels compared with L1 remains a highly controversial topic among literature. Summary Most adult deformity patients never seek nonoperative or operative treatment. Of the few that seek treatment, many can benefit from nonoperative treatment. However, in selected patients who have failed nonoperative treatment and who are candidates for surgical intervention, the literature reflects positive outcomes related to surgical intervention as compared with nonoperative treatment despite varying associated ranges in morbidity and mortality rates. If nonoperative therapy fails in addressing a patient's complaints, then an appropriate surgical procedure that relieves neural compression, corrects excessive sagittal or coronal imbalance, and results in a solidly fused, pain-free spine is warranted.