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1. Targeted Polymeric Nanoparticles for Drug Delivery to Hypoxic, Triple-Negative Breast Tumors

   https://doi.org/10.1021/acsabm.0c01336  

   Mamnoon, Babak ; Loganathan, Jagadish ; Confeld, Matthew I. ; De Fonseka, Nimesha ; Feng, Li ; Froberg, Jamie ; Choi, Yongki ; Tuvin, Daniel M. ; Sathish, Venkatachalem ; Mallik, Sanku ( December 2020 , ACS Applied Bio Materials)

   High recurrence and metastasis to vital organs are the major characteristics of triple-negative breast cancer (TNBC). Low vascular oxygen tension promotes resistance to chemo- and radiation therapy. Neuropilin-1 (NRP-1) receptor is highly expressed on TNBC cells. The tumor-penetrating iRGD peptide interacts with the NRP-1 receptor, triggers endocytosis and transcytosis, and facilitates penetration. Herein, we synthesized a hypoxia-responsive diblock PLA–diazobenzene–PEG copolymer and prepared self-assembled hypoxia-responsive polymersomes (Ps) in an aqueous buffer. The iRGD peptide was incorporated into the polymersome structure to make hypoxia-responsive iRGD-conjugated polymersomes (iPs). Doxorubicin (DOX) was encapsulated in the polymersomes to prepare both targeted and nontargeted hypoxia-responsive polymersomes (DOX-iPs and DOX-Ps, respectively). The polymeric nanoparticles released less than 30% of their encapsulated DOX within 12 h under normoxic conditions (21% oxygen), whereas under hypoxia (2% oxygen) doxorubicin release remarkably increased to over 95%. The targeted polymersomes significantly decreased TNBC cells’ viability in monolayer and spheroid cultures under hypoxia compared to normoxia. Animal studies displayed that targeted polymersomes significantly diminished tumor growth in xenograft nude mice. Overall, the targeted polymersomes exhibited potent antitumor activity in monolayer, spheroid, and animal models of TNBC. With further developments, the targeted nanocarriers discussed here might have the translational potential as drug carriers formore »the treatment of TNBC.« less
2. Microbial Community Dynamics Provide Evidence for Hypoxia during a Coral Reef Mortality Event

   https://doi.org/10.1128/aem.00347-22  

   Doyle, Shawn M. ; Self, Miabel J. ; Hayes, Joseph ; Shamberger, Kathryn E. ; Correa, Adrienne M. ; Davies, Sarah W. ; Santiago-Vázquez, Lory Z. ; Sylvan, Jason B. ( May 2022 , Applied and Environmental Microbiology)

   Villanueva, Laura (Ed.)

   ABSTRACT In July 2016, a severe coral reef invertebrate mortality event occurred approximately 200 km southeast of Galveston, Texas, at the East Flower Garden Bank, wherein ∼82% of corals in a 0.06-km 2 area died. Based on surveys of dead corals and other invertebrates shortly after this mortality event, responders hypothesized that localized hypoxia was the most likely direct cause. However, no dissolved oxygen data were available to test this hypothesis, because oxygen is not continuously monitored within the Flower Garden Banks sanctuary. Here, we quantify microbial plankton community diversity based on four cruises over 2 years at the Flower Garden Banks, including a cruise just 5 to 8 days after the mortality event was first observed. In contrast with observations collected during nonmortality conditions, microbial plankton communities in the thermocline were differentially enriched with taxa known to be active and abundant in oxygen minimum zones or that have known adaptations to oxygen limitation shortly after the mortality event (e.g., SAR324, Thioglobaceae , Nitrosopelagicus , and Thermoplasmata MGII). Unexpectedly, these enrichments were not localized to the East Bank but were instead prevalent across the entire study area, suggesting there was a widespread depletion of dissolved oxygen concentrations in the thermocline around themore »time of the mortality event. Hydrographic analysis revealed the southern East Bank coral reef (where the localized mortality event occurred) was uniquely within the thermocline at this time. Our results demonstrate how temporal monitoring of microbial communities can be a useful tool to address questions related to past environmental events. IMPORTANCE In the northwestern Gulf of Mexico in July 2016, ∼82% of corals in a small area of the East Flower Garden Bank coral reef suddenly died without warning. Oxygen depletion is believed to have been the cause. However, there was considerable uncertainty, as no oxygen data were available from the time of the event. Microbes are sensitive to changes in oxygen and can be used as bioindicators of oxygen loss. In this study, we analyze microbial communities in water samples collected over several years at the Flower Garden Banks, including shortly after the mortality event. Our findings indicate that compared to normal conditions, oxygen depletion was widespread in the deep-water layer during the mortality event. Hydrographic analysis of water masses further revealed some of this low-oxygen water likely upwelled onto the coral reef.« less
3. Hypoxia Tolerance and Metabolic Suppression in Oxygen Minimum Zone Euphausiids: Implications for Ocean Deoxygenation and Biogeochemical Cycles

   https://doi.org/doi:10.1093/icb/icw091  

   Seibel, B.A. ; Schneider, J.L. ; Kaartvedt, S. ; Wishner, K.F. ; Daly, K.L. ( August 2016 , Integrative and comparative biology)

   The effects of regional variations in oxygen and temperature levels with depth were assessed for the metabolism and hypoxia tolerance of dominant euphausiid species. The physiological strategies employed by these species facilitate prediction of changing vertical distributions with expanding oxygen minimum zones and inform estimates of the contribution of vertically migrating species to biogeochemical cycles. The migrating species from the Eastern Tropical Pacific (ETP), Euphausia eximia and Nematoscelis gracilis, tolerate a Partial Pressure (PO2) of 0.8 kPa at 10 8C (15 mM O2) for at least 12 h without mortality, while the California Current species, Nematoscelis difficilis, is incapable of surviving even 2.4 kPa PO2 (32 mM O2) for more than 3 h at that temperature. Euphausia diomedeae from the Red Sea migrates into an intermediate oxygen minimum zone, but one in which the temperature at depth remains near 22 8C. Euphausia diomedeae survived 1.6 kPa PO2 (22 mM O2) at 228C for the duration of six hour respiration experiments. Critical oxygen partial pressures were estimated for each species, and, for E. eximia, measured via oxygen consumption (2.1 kPa, 10 8C, n¼2) and lactate accumulation (1.1 kPa, 10 8C). A primary mechanism facilitating low oxygen tolerance is an ability tomore »dramatically reduce energy expenditure during daytime forays into low oxygen waters. The ETP and Red Sea species reduced aerobic metabolism by more than 50% during exposure to hypoxia. Anaerobic glycolytic energy production, as indicated by whole-animal lactate accumulation, contributed only modestly to the energy deficit. Thus, the total metabolic rate was suppressed by 49–64%. Metabolic suppression during diel migrations to depth reduces the metabolic contribution of these species to vertical carbon and nitrogen flux (i.e., the biological pump) by an equivalent amount. Growing evidence suggests that metabolic suppression is a widespread strategy among migrating zooplankton in oxygen minimum zones and may have important implications for the economy and ecology of the oceans. The interacting effects of oxygen and temperature on the metabolism of oceanic species facilitate predictions of changing vertical distribution with climate change.« less
4. A Heterogeneously Expressed Gene Family Modulates the Biofilm Architecture and Hypoxic Growth of Aspergillus fumigatus

   https://doi.org/10.1128/mBio.03579-20  

   Kowalski, Caitlin H. ; Morelli, Kaesi A. ; Stajich, Jason E. ; Nadell, Carey D. ; Cramer, Robert A. ( February 2021 , mBio)

   Doering, Tamara L. (Ed.)

   ABSTRACT The genus Aspergillus encompasses human pathogens such as Aspergillus fumigatus and industrial powerhouses such as Aspergillus niger . In both cases, Aspergillus biofilms have consequences for infection outcomes and yields of economically important products. However, the molecular components influencing filamentous fungal biofilm development, structure, and function remain ill defined. Macroscopic colony morphology is an indicator of underlying biofilm architecture and fungal physiology. A hypoxia-locked colony morphotype of A. fumigatus has abundant colony furrows that coincide with a reduction in vertically oriented hyphae within biofilms and increased low oxygen growth and virulence. Investigation of this morphotype has led to the identification of the causative gene, biofilm architecture factor A ( bafA ), a small cryptic open reading frame within a subtelomeric gene cluster. BafA is sufficient to induce the hypoxia-locked colony morphology and biofilm architecture in A. fumigatus . Analysis across a large population of A. fumigatus isolates identified a larger family of baf genes, all of which have the capacity to modulate hyphal architecture, biofilm development, and hypoxic growth. Furthermore, introduction of A. fumigatus bafA into A. niger is sufficient to generate the hypoxia-locked colony morphology, biofilm architecture, and increased hypoxic growth. Together, these data indicate the potential broadmore »impacts of this previously uncharacterized family of small genes to modulate biofilm architecture and function in clinical and industrial settings. IMPORTANCE The manipulation of microbial biofilms in industrial and clinical applications remains a difficult task. The problem is particularly acute with regard to filamentous fungal biofilms for which molecular mechanisms of biofilm formation, maintenance, and function are only just being elucidated. Here, we describe a family of small genes heterogeneously expressed across Aspergillus fumigatus strains that are capable of modifying colony biofilm morphology and microscopic hyphal architecture. Specifically, these genes are implicated in the formation of a hypoxia-locked colony morphotype that is associated with increased virulence of A. fumigatus . Synthetic introduction of these gene family members, here referred to as biofilm architecture factors, in both A. fumigatus and A. niger additionally modulates low oxygen growth and surface adherence. Thus, these genes are candidates for genetic manipulation of biofilm development in aspergilli.« less
5. ROS and hypoxia signaling regulate periodic metabolic arousal during insect dormancy to coordinate glucose, amino acid, and lipid metabolism

   https://doi.org/10.1073/pnas.2017603118  

   Chen, Chao ; Mahar, Rohit ; Merritt, Matthew E. ; Denlinger, David L. ; Hahn, Daniel A. ( December 2020 , Proceedings of the National Academy of Sciences)

   Metabolic suppression is a hallmark of animal dormancy that promotes overall energy savings. Some diapausing insects and some mammalian hibernators have regular cyclic patterns of substantial metabolic depression alternating with periodic arousal where metabolic rates increase dramatically. Previous studies, largely in mammalian hibernators, have shown that periodic arousal is driven by an increase in aerobic mitochondrial metabolism and that many molecules related to energy metabolism fluctuate predictably across periodic arousal cycles. However, it is still not clear how these rapid metabolic shifts are regulated. We first found that diapausing flesh fly pupae primarily use anaerobic glycolysis during metabolic depression but engage in aerobic respiration through the tricarboxylic acid cycle during periodic arousal. Diapausing pupae also clear anaerobic by-products and regenerate many metabolic intermediates depleted in metabolic depression during arousal, consistent with patterns in mammalian hibernators. We found that decreased levels of reactive oxygen species (ROS) induced metabolic arousal and elevated ROS extended the duration of metabolic depression. Our data suggest ROS regulates the timing of metabolic arousal by changing the activity of two critical metabolic enzymes, pyruvate dehydrogenase and carnitine palmitoyltransferase I by modulating the levels of hypoxia inducible transcription factor (HIF) and phosphorylation of adenosine 5′-monophosphate-activated protein kinase (AMPK).more »Our study shows that ROS signaling regulates periodic arousal in our insect diapasue system, suggesting the possible importance ROS for regulating other types of of metabolic cycles in dormancy as well.

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