Evaluating the effectiveness of Mangrove rehabilitation: A novel approach for sustainable coastal management.

We used UAV-LiDAR technology and other advanced remote sensing techniques to evaluate mangrove rehabilitation projects along the eroding shoreline of the Upper Gulf of Thailand. Our results delineate the necessary biophysical conditions for successfully rehabilitating mangroves, establishing optimal conditions under which mangroves can naturally re-establish and thrive. Furthermore, we investigated the effectiveness of different coastal defense structures in fostering mangrove recolonization. Our analysis shows that nearshore breakwaters markedly outperform submerged breakwaters and bamboo fences, with a success rate of over 65% by significantly reducing wave energy that aids sediment trapping. These findings suggest that refinements in the configuration of coastal structures, including the elevation of breakwater crests and selective deployment of bamboo fences, will enhance mangrove rehabilitation success. These insights affirm the role of UAV-LiDAR surveys for optimizing mangrove restoration initiatives, thereby facilitating sustainable development for coastlines plagued by erosion. The insights gleaned offer a blueprint for bolstering the success rate of mangrove rehabilitation projects, directing them toward sustainable coastal development.

Genetic Silencing of AKT Induces Melanoma Cell Death via mTOR Suppression.

Aberrant activation of the PI3K-AKT pathway is common in many cancers, including melanoma, and AKT1, 2 and 3 (AKT1-3) are bona fide oncoprotein kinases with well-validated downstream effectors. However, efforts to pharmacologically inhibit AKT have proven to be largely ineffective. In this study, we observed paradoxical effects following either pharmacologic or genetic inhibition of AKT1-3 in melanoma cells. Although pharmacological inhibition was without effect, genetic silencing of all three AKT paralogs significantly induced melanoma cell death through effects on mTOR. This phenotype was rescued by exogenous AKT1 expression in a kinase-dependent manner. Pharmacological inhibition of PI3K and mTOR with a novel dual inhibitor effectively suppressed melanoma cell proliferation in vitro and inhibited tumor growth in vivo. Furthermore, this single-agent-targeted therapy was well-tolerated in vivo and was effective against MAPK inhibitor-resistant patient-derived melanoma xenografts. These results suggest that inhibition of PI3K and mTOR with this novel dual inhibitor may represent a promising therapeutic strategy in this disease in both the first-line and MAPK inhibitor-resistant setting.

Mannose-Coated Reconstituted Lipoprotein Nanoparticles for the Targeting of Tumor-Associated Macrophages: Optimization, Characterization, and In Vitro Evaluation of Effectiveness.

Reconstituted high-density lipoprotein nanoparticles (rHDL NPs) have been utilized as delivery vehicles to a variety of targets, including cancer cells. However, the modification of rHDL NPs for the targeting of the pro-tumoral tumor-associated macrophages (TAMs) remains largely unexplored. The presence of mannose on nanoparticles can facilitate the targeting of TAMs which highly express the mannose receptor at their surface. Here, we optimized and characterized mannose-coated rHDL NPs loaded with 5,6-dimethylxanthenone-4-acetic acid (DMXAA), an immunomodulatory drug. Lipids, recombinant apolipoprotein A-I, DMXAA, and different amounts of DSPE-PEG-mannose (DPM) were combined to assemble rHDL-DPM-DMXAA NPs. The introduction of DPM in the nanoparticle assembly altered the particle size, zeta potential, elution pattern, and DMXAA entrapment efficiency of the rHDL NPs. Collectively, the changes in physicochemical characteristics of rHDL NPs upon the addition of the mannose moiety DPM indicated that the rHDL-DPM-DMXAA NPs were successfully assembled. The rHDL-DPM-DMXAA NPs induced an immunostimulatory phenotype in macrophages pre-exposed to cancer cell-conditioned media. Furthermore, rHDL-DPM NPs delivered their payload more readily to macrophages than cancer cells. Considering the effects of the rHDL-DPM-DMXAA NPs on macrophages, the rHDL-DPM NPs have the potential to serve as a drug delivery platform for the selective targeting of TAMs.

A phase I open-label study of the safety and efficacy of apatinib (rivoceranib) administered to patients with advanced malignancies to improve sensitivity to pembrolizumab in the second- or later-line setting (APPEASE).

OBJECTIVE: APPEASE is a phase I study to assess the safety, dosing, and efficacy of rivoceranib (a selective, small-molecule inhibitor of VEGFR2) in combination with pembrolizumab. We aimed to treat patients with metastatic malignancies who have progressed through at least first-line therapy, with pembrolizumab 200 mg every 3 weeks, as well as escalating doses of rivoceranib until disease progression or unacceptable toxicity. RESULTS: Five patients were enrolled on the starting dose of rivoceranib 300 mg once daily. There were no dose-limiting toxicities observed in combination with pembrolizumab. The dose of rivoceranib was not escalated due to study closure. We note a treatment related grade 3 adverse event (AE) rate of 40%, predominantly in urothelial cancer patients, with no deaths related to treatment related AEs. The disease control rate was 75% (3 of 4) and the median progression free survival (PFS) was 3.6 months. Tumor shrinkage was noted in patients who were previously progressing on pembrolizumab alone. Apatinib 300 mg is safe and demonstrates anti-tumor activity in advanced solid tumors in combination with pembrolizumab. Further dose escalation and efficacy need to be investigated in larger disease-specific patient populations. TRIAL REGISTRATION NUMBER: Clinical trial registration number: NCT03407976. Date of registration: January 17, 2018.

Effectiveness of grey and green engineered solutions for protecting the low-lying muddy coast of the Chao Phraya Delta, Thailand.

Coastal protection measures can be categorized into grey and green solutions in terms of their ecosystem impacts. As the use of grey solutions has become a serious issue due to environmental consequences during the last few decades, green/nature-based solutions have become prioritized. This study evaluates the effectiveness of grey and green solutions applied along the eastern Chao Phraya Delta (ECPD) based on historical shoreline change analysis and coastal observations using Light Detection and Ranging technology. The results from shoreline analysis indicate that nearshore breakwaters installed 100-250 m from the shoreline have successfully reclaimed the coastline with a sedimentation rate of 17-23 cm/y. Meanwhile, sand-sausage-submerged breakwaters were ineffective at stabilizing the coastline during 2002-2010 due to land subsidence. With a low subsidence rate, the rubble-mound-submerged breakwaters can reduce the shoreline retreat rate with a vertical deposition rate of about 5 cm/y. In contrast, use of a bamboo fence, a green solution widely used along muddy coasts, traps sediment at a rate of less than 1.3 cm/y and typically lasts only for 2-3 years after installation. Decomposed bamboo causes environmental degradation so local communities disapprove of the approach. Results reveal that grey solutions are more effective for stabilizing the ECPD coastline and result in less coastal environmental impact than the nature-based solution using a bamboo fence.

A global assessment of the mixed layer in coastal sediments and implications for carbon storage.

The sediment-water interface in the coastal ocean is a highly dynamic zone controlling biogeochemical fluxes of greenhouse gases, nutrients, and metals. Processes in the sediment mixed layer (SML) control the transfer and reactivity of both particulate and dissolved matter in coastal interfaces. Here we map the global distribution of the coastal SML based on excess 210Pb (210Pbex) profiles and then use a neural network model to upscale these observations. We show that highly dynamic regions such as large estuaries have thicker SMLs than most oceanic sediments. Organic carbon preservation and SMLs are inversely related as mixing stimulates oxidation in sediments which enhances organic matter decomposition. Sites with SML thickness >60 cm usually have lower organic carbon accumulation rates (<50 g C m-2 yr-1) and total organic carbon/specific surface area ratios (<0.4 mg m-2). Our global scale observations reveal that reworking can accelerate organic matter degradation and reduce carbon storage in coastal sediments.

Zam Is a Redox-Regulated Member of the RNB-Family Required for Optimal Photosynthesis in Cyanobacteria.

The zam gene mediating resistance to acetazolamide in cyanobacteria was discovered thirty years ago during a drug tolerance screen. We use phylogenetics to show that Zam proteins are distributed across cyanobacteria and that they form their own unique clade of the ribonuclease II/R (RNB) family. Despite being RNB family members, multiple sequence alignments reveal that Zam proteins lack conservation and exhibit extreme degeneracy in the canonical active site-raising questions about their cellular function(s). Several known phenotypes arise from the deletion of zam, including drug resistance, slower growth, and altered pigmentation. Using room-temperature and low-temperature fluorescence and absorption spectroscopy, we show that deletion of zam results in decreased phycocyanin synthesis rates, altered PSI:PSII ratios, and an increase in coupling between the phycobilisome and PSII. Conserved cysteines within Zam are identified and assayed for function using in vitro and in vivo methods. We show that these cysteines are essential for Zam function, with mutation of either residue to serine causing phenotypes identical to the deletion of Zam. Redox regulation of Zam activity based on the reversible oxidation-reduction of a disulfide bond involving these cysteine residues could provide a mechanism to integrate the 'central dogma' with photosynthesis in cyanobacteria.

Prior Exposure to Coxsackievirus A21 Does Not Mitigate Oncolytic Therapeutic Efficacy.

Oncolytic viruses (OVs) are being developed as a type of immunotherapy and have demonstrated durable tumor responses and clinical efficacy. One such OV, Coxsackievirus A21 (CVA21), exhibited therapeutic efficacy in early phase clinical trials, demonstrating the ability to infect and kill cancer cells and stimulate anti-tumor immune responses. However, one of the major concerns in using this common cold virus as a therapeutic is the potential for innate and adaptive immune responses to mitigate the benefits of viral infection, particularly in individuals that have been exposed to coxsackievirus prior to treatment. In this study, we assess melanoma responses to CVA21 in the absence or presence of prior exposure to the virus. Melanomas were transplanted into naïve or CVA21-immunized C57BL6 mice and the mice were treated with intratumoral (IT) CVA21. We find that prior exposure to CVA21 does not dramatically affect tumor responses, nor does it alter overall survival. Our results suggest that prior exposure to coxsackievirus is not a critical determinant of patient selection for IT CVA21 interventions.

An analysis of the factors responsible for the shoreline retreat of the Chao Phraya Delta (Thailand).

Deltas are inherently low-lying structures and thus subject to large threats due to sea level rise, erosion and other coastal processes. The shorelines in many deltas around the world are now retreating and most cases appear to result from a decreasing sediment supply as a consequence of upstream dam construction. We present here results of an investigation of riverine sediment fluxes, coastal retreat, and coastal sediment accumulation in the Chao Phraya River and Delta (Thailand). This deltaic shoreline has one of the highest rates of shoreline retreat in the world. Surprisingly, our results show that in spite of the construction of two large storage dams, one on the Ping River (Bhumibol Dam, 1964) and the other on the Nan River (Sirikit Dam, 1972) that merge to form the Chao Phraya, sediment accumulation in the delta was actually higher over the last several decades than prior to dam construction. The recent higher rates of sediment accumulation, based on 210Pb dating, appear to be the result of increased sediment supply in the lower reaches of the river relating to expansion of aquaculture and other activities in the delta beginning in the 1970s. We also show that mangrove removal, in order to further develop shrimp farming, charcoal production, and other pursuits, was not responsible for most of the shoreline erosion. Rather, subsidence, mainly induced by groundwater withdrawal, together with worldwide sea level rise appears to be the main factor affecting the very rapid shoreline retreat of the Chao Phraya Delta.

Maternal Obesity and Western-Style Diet Impair Fetal and Juvenile Offspring Skeletal Muscle Insulin-Stimulated Glucose Transport in Nonhuman Primates.

Infants born to mothers with obesity have a greater risk for childhood obesity and metabolic diseases; however, the underlying biological mechanisms remain poorly understood. We used a Japanese macaque model to investigate whether maternal obesity combined with a Western-style diet (WSD) impairs offspring muscle insulin action. Adult females were fed a control or WSD prior to and during pregnancy through lactation, and offspring subsequently weaned to a control or WSD. Muscle glucose uptake and signaling were measured ex vivo in fetal (n = 5-8/group) and juvenile (n = 8/group) offspring. In vivo signaling was evaluated after an insulin bolus just prior to weaning (n = 4-5/group). Maternal WSD reduced insulin-stimulated glucose uptake and impaired insulin signaling at the level of Akt phosphorylation in fetal muscle. In juvenile offspring, insulin-stimulated glucose uptake was similarly reduced by both maternal and postweaning WSD and corresponded to modest reductions in insulin-stimulated Akt phosphorylation relative to controls. We conclude that maternal WSD leads to a persistent decrease in offspring muscle insulin-stimulated glucose uptake even in the absence of increased offspring adiposity or markers of systemic insulin resistance. Switching offspring to a healthy diet did not reverse the effects of maternal WSD on muscle insulin action, suggesting earlier interventions may be warranted.

Does submarine groundwater discharge contribute to summer hypoxia in the Changjiang (Yangtze) River Estuary?

The Changjiang (Yangtze) River Estuary (CJE) is one of the largest and most intense seasonal hypoxic zones in the world. Here we examine the possibility that submarine groundwater discharge (SGD) may contribute to the summer hypoxia. Spatial distributions of bottom water 222Rn suggest a hotspot discharge area in the northern section of the CJE. SGD fluxes were estimated based on a 222Rn mass balance model and were found to range from 0.002 ± 0.004 to 0.022 ± 0.011 m3/m2/day. Higher SGD fluxes were observed during summer hypoxia period. The well-developed overlap of the distribution patterns for SGD flux and dissolved oxygen (DO) implies that SGD could be an important contributor to summer hypoxia in the region off the CJE. We suggest that SGD contributes to the seasonal hypoxia either: (1) directly via discharge of anoxic groundwaters together with reducing substances; and/or (2) indirectly by delivering excess nutrients that stimulate primary productivity with consequent consumption of DO during organic matter decomposition.

ASA Suppresses PGE2 in Plasma and Melanocytic Nevi of Human Subjects at Increased Risk for Melanoma.

Potential anti-inflammatory and anticarcinogenic effects of aspirin (ASA) may be suitable for melanoma chemoprevention, but defining biomarkers in relevant target tissues is prerequisite to performing randomized controlled chemoprevention trials. We conducted open-label studies with ASA in 53 human subjects with melanocytic nevi at increased risk for melanoma. In a pilot study, 12 subjects received a single dose (325 mg) of ASA; metabolites salicylate, salicylurate, and gentisic acid were detected in plasma after 4-8 h, and prostaglandin E2 (PGE2) was suppressed in both plasma and nevi for up to 24 h. Subsequently, 41 subjects received either 325 or 81 mg ASA (nonrandomized) daily for one week. ASA metabolites were consistently detected in plasma and nevi, and PGE2 levels were significantly reduced in both plasma and nevi. Subchronic ASA dosing did not affect 5" adenosine monophosphate-activated protein kinase (AMPK) activation in nevi or leukocyte subsets in peripheral blood, although metabolomic and cytokine profiling of plasma revealed significant decreases in various (non-ASA-derived) metabolites and inflammatory cytokines. In summary, short courses of daily ASA reduce plasma and nevus PGE2 and some metabolites and cytokines in plasma of human subjects at increased risk for melanoma. PGE2 may be a useful biomarker in blood and nevi for prospective melanoma chemoprevention studies with ASA.

Tracing underground sources of pollution to coastal waters off Map Ta Phut, Rayong, Thailand.

We explored the possibility that an underground pathway, "submarine groundwater discharge" (SGD), may contribute to the observed coastal contamination from a large industrial complex on the Gulf of Thailand. Three surveys were performed to map the area for the natural groundwater tracers radon, thoron and salinity. The results from all three surveys were internally consistent showing a point source adjacent to a large pier that serves the complex. It may be that a piling, driven into the ground to support the pier, intercepted a shallow aquifer and this resulted in an underground pathway between land and sea. Some low-density sediments are enriched in radium, we suspect from fly ash from a nearby power plant. Water quality parameters showed that total petroleum hydrocarbons (TPHs) correlated strongly to nitrite, dissolved inorganic phosphate and silica, indicating a common source. Data analysis shows that diffuse seepage accounts for more discharge than the point source.

Radium isotopes-suspended sediment relationships in a muddy river.

Radium isotopes are known to be excellent geochemical tracers for study of oceanographic processes. We show here that radium isotopes can also be used to assess adsorption/desorption and transport processes in rivers. The Yellow River (Huanghe), one of the longest, most turbid and heavily regulated rivers in the world, is used as an example. We first investigated the temporal and spatial behavior of radium isotopes (224Ra and 226Ra) in the lower reaches of the river, and found that this zone displayed some of the highest known riverine radium concentrations and fluxes in the world. Suspended particulate matter (SPM) is shown to be the dominant factor controlling radium activities. Laboratory simulation experiments showed that radium desorption from SPM obeys an exponential relationship in fresh water (S = 0). When salinities are >10, the increase in radium concentration follows a linear increase with respect to the amounts of SPM added. Significantly higher radium concentrations (3-5 times), especially for short-lived 224Ra, were observed during the "Water-Sediment Regulation Scheme" (WSRS), an annual management event when ∼15%-55% of the annual water discharge and ∼30%-75% of the annual sediment load are released from a reservoir to control sedimentation in the Yellow River. The radium fluxes during WSRS periods (∼2 weeks long) accounted for more than half of the entire annual load during the periods studied. Sediment erosion and pore water release are also thought to be important processes supplying radium to the river. After a WSRS, Ra desorption from SPM increases and becomes the prevailing process.

Applications of radon and radium isotopes to determine submarine groundwater discharge and flushing times in Todos os Santos Bay, Brazil.

Todos os Santos Bay (BTS) is the 2nd largest bay in Brazil and an important resource for the people of the State of Bahia. We made measurements of radon and radium in selected areas of the bay to evaluate if these tracers could provide estimates of submarine groundwater discharge (SGD) and flushing times of the Paraguaçu Estuary and BTS. We found that there were a few areas along the eastern and northeastern shorelines that displayed relatively high radon and low salinities, indicating possible sites of enhanced SGD. A time-series mooring over a tidal cycle at Marina do Bonfim showed a systematic enrichment of the short-lived radium isotopes 223Ra and 224Ra during the falling tide. Assuming that the elevated radium isotopes were related to SGD and using measured radium activities from a shallow well at the site, we estimated groundwater seepage at about 70 m3/day per unit width of shoreline. Extrapolating to an estimated total shoreline length provided a first approximation of total (fresh + saline) SGD into BTS of 300 m3/s, about 3 times the average river discharge into the bay. Just applying the shoreline lengths from areas identified with high radon and reduced salinity results in a lower SGD estimate of 20 m3/s. Flushing times of the Paraguaçu Estuary were estimated at about 3-4 days based on changing radium isotope ratios from low to high salinities. The flushing time for the entire BTS was also attempted using the same approach and resulted in a surprisingly low value of only 6-8 days. Although physical oceanographic models have proposed flushing times on the order of months, a simple tidal prism calculation provided results in the range of 4-7 days, consistent with the radium approach. Based on these initial results, we recommend a strategy for refining both SGD and flushing time estimates.

Optimizing laboratory-based radon flux measurements for sediments.

Radon flux via diffusion from sediments and other materials may be determined in the laboratory by circulating air through the sample and a radon detector in a closed loop. However, this approach is complicated by the necessity of having to determine the total air volume in the system and accounting for any small air leaks that can arise if using extended measurement periods. We designed a simple open-loop configuration that includes a measured mass of wet sediment and water inside a gas-tight reaction flask connected to a drying system and a radon-in-air analyzer. Ambient air flows through two charcoal columns before entering the reaction vessel to eliminate incoming radon. After traveling through the reaction flask, the air passes the drier and the radon analyzer and is then vented. After some time, the radon activity will reach a steady state depending upon the airflow rate. With this approach, the radon flux via diffusion is simply the product of the steady-state radon activity (Bq/m(3)) multiplied by the airflow rate (mL/min). We demonstrated that this setup could produce good results for materials that produce relatively high radon fluxes. We also show that a modified closed system approach, including radon removal of the incoming air by charcoal filtration in a bypass, can produce very good results including samples with very low emission rates.

Evolution of an ancient protein function involved in organized multicellularity in animals.

To form and maintain organized tissues, multicellular organisms orient their mitotic spindles relative to neighboring cells. A molecular complex scaffolded by the GK protein-interaction domain (GKPID) mediates spindle orientation in diverse animal taxa by linking microtubule motor proteins to a marker protein on the cell cortex localized by external cues. Here we illuminate how this complex evolved and commandeered control of spindle orientation from a more ancient mechanism. The complex was assembled through a series of molecular exploitation events, one of which - the evolution of GKPID's capacity to bind the cortical marker protein - can be recapitulated by reintroducing a single historical substitution into the reconstructed ancestral GKPID. This change revealed and repurposed an ancient molecular surface that previously had a radically different function. We show how the physical simplicity of this binding interface enabled the evolution of a new protein function now essential to the biological complexity of many animals.

AKT1 Activation Promotes Development of Melanoma Metastases.

Metastases are the major cause of melanoma-related mortality. Previous studies implicating aberrant AKT signaling in human melanoma metastases led us to evaluate the effect of activated AKT1 expression in non-metastatic BRAF(V600E)/Cdkn2a(Null) mouse melanomas in vivo. Expression of activated AKT1 resulted in highly metastatic melanomas with lung and brain metastases in 67% and 17% of our mice, respectively. Silencing of PTEN in BRAF(V600E)/Cdkn2a(Null) melanomas cooperated with activated AKT1, resulting in decreased tumor latency and the development of lung and brain metastases in nearly 80% of tumor-bearing mice. These data demonstrate that AKT1 activation is sufficient to elicit lung and brain metastases in this context and reveal that activation of AKT1 is distinct from PTEN silencing in metastatic melanoma progression. These findings advance our knowledge of the mechanisms driving melanoma metastasis and may provide valuable insights for clinical management of this disease.