•
Introduction
•
Intracellular pH regulation controls energy balance and cell proliferation: chemical and biological proof of principle
‐
Chemical proof of principle
‐
Biological proof of ...principle: the role of the Na+/H+ exchanger‐1
•
Oncogene activation and transformation cause acidosis
‐
Warburg effect (aerobic glycolysis)
‐
Inhibition of tumour suppressor genes and oncogene activation drive the ‘Warburg effect’ and cause acidosis
‐
Neoplastic transformation drives intracellular alkalinization and extracellular acidification through the activation and up‐regulation of pHi‐regulating systems
•
Hypoxia promotes acidosis by shifting from oxidative phosphorylation to glycolytic metabolism
‐
HIF mediates cellular adaptation to low oxygen availability
‐
HIF‐induced metabolic reprogramming in response to tumour hypoxia causes acidosis
‐
Acidosis may affect HIF‐α stabilization and on HIF‐induced gene regulation
•
Hypoxia enhances the expression and activity of pHi‐regulating systems to promote cell survival and invasion
‐
Hypoxia increases NHE‐1 expression and activity
‐
The hypoxia‐induced membrane‐associated carbonic anhydrases are key enzymes involved in pH homeostasis, cell survival and migration in a hypoxic/acidic microenvironment
‐
CAIX regulation and expression
‐
CAXII regulation and expression
‐
The activity and functions of CAIX and CAXII
‐
The hypoxia‐induced monocarboxylate transporter MCT4, the constitutively expressed MCT1 and their chaperone CD147 are key plasma‐membrane proteins involved in pH regulation, energy balance, tumour progression and metastasis
‐
MCT regulation, expression, structure and implication of their chaperone CD147
‐
The MCT1, MCT4 and CD147 activity and functions
•
Strategies taking advantage of changes in the oxygen level, energy balance and pH homeostasis to target primary tumours and metastases
‐
Decreasing the pHi of hypoxic cells of the primary tumour by inhibiting key pHi‐regulating systems to collapse ATP production
‐
Increasing pHo and the extracellular buffering capacity in targeting metastasis and reducing multidrug resistance
•
Conclusion
Maintenance of cellular pH homeostasis is fundamental to life. A number of key intracellular pH (pHi) regulating systems including the Na+/H+ exchangers, the proton pump, the monocarboxylate transporters, the HCO3− transporters and exchangers and the membrane‐associated and cytosolic carbonic anhydrases cooperate in maintaining a pHi that is permissive for cell survival. A common feature of tumours is acidosis caused by hypoxia (low oxygen tension). In addition to oncogene activation and transformation, hypoxia is responsible for inducing acidosis through a shift in cellular metabolism that generates a high acid load in the tumour microenvironment. However, hypoxia and oncogene activation also allow cells to adapt to the potentially toxic effects of an excess in acidosis. Hypoxia does so by inducing the activity of a transcription factor the hypoxia‐inducible factor (HIF), and particularly HIF‐1, that in turn enhances the expression of a number of pHi‐regulating systems that cope with acidosis. In this review, we will focus on the characterization and function of some of the hypoxia‐inducible pH‐regulating systems and their induction by hypoxic stress. It is essential to understand the fundamentals of pH regulation to meet the challenge consisting in targeting tumour metabolism and acidosis as an anti‐tumour approach. We will summarize strategies that take advantage of intracellular and extracellular pH regulation to target the primary tumour and metastatic growth, and to turn around resistance to chemotherapy and radiotherapy.
Clinical Characteristics of Covid-19 in New York City Goyal, Parag; Choi, Justin J; Pinheiro, Laura C ...
New England journal of medicine/The New England journal of medicine,
06/2020, Letnik:
382, Številka:
24
Journal Article
Signal Transducer and Activator of Transcription 3 (STAT3) has recently been shown to be involved in bone development and has been implicated in bone diseases, such as Job’s Syndrome. Bone growth and ...changes have been known for many years to differ between sexes with male bones tending to have higher bone mass than female bones and older females tending to lose bone mass at faster rates than older males. Previous studies using conditional knock mice with Stat3 specifically deleted from the osteoblasts showed both sexes exhibited decreased bone mineral density (BMD) and strength. Using the Cre-Lox system with Cathepsin K promotor driving Cre to target the deletion of the Stat3 gene in mature osteoclasts (STAT3-cKO mice), we observed that 8-week old STAT3-cKO female femurs exhibited significantly lower BMD and bone mineral content (BMC) compared to littermate control (CN) females. There were no differences in BMD and BMC observed between male knock-out and male CN femurs. However, micro-computed tomography (μCT) analysis showed that both male and female STAT3-cKO mice had significant decreases in bone volume/tissue volume (BV/TV). Bone histomorphometry analysis of the distal femur, further revealed a decrease in bone formation rate and mineralizing surface/bone surface (MS/BS) with a significant decrease in osteoclast surface in female, but not male, STAT3-cKO mice. Profiling gene expression in an osteoclastic cell line with a knockdown of STAT3 showed an upregulation of a number of genes that are directly regulated by estrogen receptors. These data collectively suggest that regulation of STAT3 differs in male and female osteoclasts and that inactivation of STAT3 in osteoclasts affects bone turnover more in females than males, demonstrating the complicated nature of STAT3 signaling pathways in osteoclastogenesis. Drugs targeting the STAT3 pathway may be used for treatment of diseases such as Job’s Syndrome and osteoporosis.
Objective: Motivation is a barrier to physical activity (PA) among African American (AA) women, but past studies have implemented a "one-size-fits-all" approach and have not addressed differences in ...autonomous motivation. This pilot randomized controlled trial assessed the preliminary efficacy of "Developing Real Incentives and Volition for Exercise," a community- and theory-based intervention, which evaluated whether a motivationally matched (vs. a nonmatched) intervention increases daily total PA. Method: In total, 68 AA women (50.72 ± 13.66 years; 86.8% with obesity) were randomized to an 8-week challenge-focused program (targeted toward high autonomous motivation) or rewards-focused program (targeted toward low autonomous motivation). Randomization was stratified by baseline autonomous motivation. FitBits were used during the intervention to promote self-monitoring (both programs) and social connectedness (challenge program only). Results: Both programs retained ≥80% of participants. Process evaluation revealed high attendance, dose, and fidelity (both programs). However, contrary to expectations, across all motivational levels (low and high autonomous), the challenge-focused intervention resulted in a greater increase in total daily PA (primary outcome), with an average increase of 17.9 min in the challenge-focused intervention versus an average decrease of 8.55 min in the rewards-focused intervention. An exploratory follow-up analysis revealed that engagement with the FitBit mobile app predicted greater PA at postintervention in the challenge-focused program. Conclusions: A team-based approach targeting social connectedness, enjoyment of PA, and positive intragroup competition is a promising approach for promoting PA among AA women. These findings are used to guide a discussion on best practices for engaging AA women in future behavioral interventions.
What is the public health significance of this article?
Across differences in motivation, a team-based model is a promising approach for promoting PA among AA women. Delivering programs within community-based setting, using positive group competition, and a mobile app to promote social connectedness are suggested best practices for engaging AA women in future interventions.
Talc is commonly found in the cores of exhumed faults and may be important to the dynamics of slip in active fault zones. To understand the rheology of talc at conditions relevant to subduction ...zones, we conducted torsional deformation experiments at high pressure (1 GPa) and temperatures (450–500°C). Scanning Transmission Electron Microscope imaging revealed a marked decrease in grain size with increasing strain, in addition to the development of grain kinking and nanoporosity. The similarity of these microstructures to talc deformed in natural faults and low‐pressure experiments indicates that the dominant deformation mechanisms of talc are similar across a wide range of depths. We conclude that frictional processes remain an important control on talc rheology even under high normal stresses. However, deformation‐induced porosity could enhance the percolation of high‐pressure or reactive fluids through talc‐rich lithologies.
Plain Language Summary
Talc, an extremely weak mineral commonly observed in natural faults, likely plays an important role in controlling how earthquake‐generating faults slip. We performed high pressure deformation experiments on a natural talc sample to help understand the role of talc at depth in large faults. Many minerals will undergo a change in deformation style as pressure and temperature increase, from a mechanism controlled by friction to a mechanism controlled by defects within the crystal lattice. Conversely, our findings indicate that talc does not experience a change in deformation mechanism at high pressure and temperature, with friction remaining an important control on talc deformation across all our experiments. This suggests that talc remains brittle throughout the seismogenic zone, including the region of tremor and slow slip. However, we also observed that as strain in the talc increased so did the generation of pore space in the samples. This could increase permeability, allowing fluids to migrate more readily through deformed talc.
Key Points
Microstructures of deformed talc indicate that talc retains a frictional control on deformation at high pressure and temperature
Constant indentation hardnesses with respect to strain suggest that strain‐induced talc microstructures do not affect material strength
Nanoporosity generated at high strains could accommodate fluids in fault zones
Research groups around the world are investigating tin (II) monosulfide (SnS) via various deposition methods and heterostructures for thin film solar cells. The maximum achieved efficiency has yet to ...reach 5% despite the promising properties of SnS. SnS devices have achieved high short-circuit current densities near 20A/cm2, but open-circuit voltage and fill factor are significantly lower than models predict. The multi-valency of tin, complex Sn–S phase diagram, and layered nature of SnS result in a complex system and large variability in the microstructure of the material. Microstructure growth is largely dependent on the deposition method, thus impacting optoelectronic properties. As a result, thin film SnS made by different processing methods cannot be compared without first considering the differences in microstructure. This review evaluates SnS, including theoretical and experimental work, and its progress as a photovoltaic absorber. Single crystal and thin film growth methods as well as the properties of the material are reviewed. Solar cell structure, back contact metals and doping are evaluated to summarize the progress in implementing SnS into devices. The challenge of sulfur volatility is a serious issue for producing high-quality SnS, and is not weighted enough in the literature. In addition, the impact of device processing following SnS deposition is not considered in any studies. The best future approach for SnS-based devices will consider sulfur content a priority, and investigate the impacts of device processing on the SnS layer.
Protein-based therapeutics represent a rapidly growing segment of approved disease treatments. Successful intracellular delivery of proteins is an important precondition for expanded in vivo and in ...vitro applications of protein therapeutics. Direct modification of proteins and peptides for improved cytosolic translocation are a promising method of increasing delivery efficiency and expanding the viability of intracellular protein therapeutics. In this Review, we present recent advances in both synthetic and genetic protein modifications for intracellular delivery. Active endocytosis-based and passive internalization pathways are discussed, followed by a review of modification methods for improved cytosolic delivery. After establishing how proteins can be modified, general strategies for facilitating intracellular delivery, such as chemical supercharging or inclusion of cell-penetrating motifs, are covered. We then outline protein modifications that promote endosomal escape. We finally examine the delivery of two potential classes of therapeutic proteins, antibodies and associated antibody fragments, and gene editing proteins, such as cas9.
A central component of the public health strategy to control the COVID-19 pandemic involves encouraging mask wearing and social distancing to protect individuals from acquiring and transmitting the ...virus.
This study aims to understand the psychological factors that drive adoption or rejection of these protective behaviors, which can inform public health interventions to control the pandemic.
We conducted an online survey of a representative sample of 1074 US adults and assessed three novel potential predictors of COVID-19 behaviors: trait reactance, COVID-19 conspiracy beliefs, and COVID-19 apocalypse beliefs. Key outcomes (dependent variables) included an index of COVID-19 protective behaviors, the number of trips taken from the home, and COVID-19 knowledge.
In bivariate analyses, all three predictors were significantly correlated in the hypothesized direction with the three COVID-19 outcomes. Specifically, each predictor was negatively (P<.01) correlated with the COVID-19 protective behaviors index and COVID-19 knowledge score, and positively correlated with trips taken from home per week (more of which was considered higher risk). COVID-19 protective behaviors and COVID-19 knowledge were significantly lower in the top median compared to the bottom median for all three predictors. In general, these findings remained significant after adjusting for all novel predictors plus age, gender, income, education, race, political party, and religiosity. Self-identified Republicans (vs other political affiliations) reported the highest values for each of the novel predictors.
This study can inform the development of health communication interventions to encourage the adoption of COVID-19 protective behaviors. Interestingly, we found that higher scores of all three novel predictors were associated with lower COVID-19 knowledge, suggesting that lack of an accurate understanding of the virus may be driving some of these attitudes; although, it is also possible that these attributes may interfere with one's willingness or ability to seek and absorb accurate health information. These individuals may be particularly immune to accepting new information and yielding their beliefs. Health communication professionals may apply lessons learned from countering similar beliefs around climate change and vaccine hesitancy. Messages designed for individuals prone to reactance may be more effective if they minimize controlling language and emphasize the individual's independence in adopting these behavioral recommendations. Messaging for those who possess conspiracy beliefs should similarly not assume that providing evidence contrary to these beliefs will alone alter behavior. Other communication techniques such as rolling with resistance, a strategy used in motivational interviewing, may be helpful. Messaging for those with apocalyptic beliefs may require using religious leaders as the message source and using scripture that would support the adoption of COVID-19 protection behaviors.
PDF
