Photosymbiosis for Biomedical Applications

Without the sustained provision of adequate levels of oxygen by the cardiovascular system, the tissues of higher animals are incapable of maintaining normal metabolic activity, and hence cannot survive. The consequence of this evolutionarily suboptimal design is that humans are dependent on cardiovascular perfusion, and therefore highly susceptible to alterations in its normal function. However, hope may be at hand. "Photosynthetic strategies," based on the recognition that photosynthesis is the source of all oxygen, offer a revolutionary and promising solution to pathologies related to tissue hypoxia. These approaches, which have been under development over the past 20 years, seek to harness photosynthetic microorganisms as a local and controllable source of oxygen to circumvent the need for blood perfusion to sustain tissue survival. To date, their applications extend from thein vitrocreation of artificial human tissues to the photosynthetic maintenance of oxygen-deprived organs bothin vivoandex vivo, while their potential use in other medical approaches has just begun to be explored. This review provides an overview of the state of the art of photosynthetic technologies and its innovative applications, as well as an expert assessment of the major challenges and how they can be addressed

Sox9-regulated cell plasticity in colorectal metastasis is attenuated by rapamycin

The cancer stem cell (CSC) hypothesis proposes a hierarchical organization of tumors, in which stem-like cells sustain tumors and drive metastasis. The molecular mechanisms underlying the acquisition of CSCs and metastatic traits are not well understood. SOX9 is a transcription factor linked to stem cell maintenance and commonly overexpressed in solid cancers including colorectal cancer. In this study, we show that SOX9 levels are higher in metastatic (SW620) than in primary colorectal cancer cells (SW480) derived from the same patient. This elevated expression correlated with enhanced self-renewal activity. By gain and loss-of-function studies in SW480 and SW620 cells respectively, we reveal that SOX9 levels modulate tumorsphere formation and self-renewal ability in vitro and tumor initiation in vivo. Moreover, SOX9 regulates migration and invasion and triggers the transition between epithelial and mesenchymal states. These activities are partially dependent on SOX9 post-transcriptional modifications. Importantly, treatment with rapamycin inhibits self-renewal and tumor growth in a SOX9- dependent manner. These results identify a functional role for SOX9 in regulating colorectal cancer cell plasticity and metastasis, and provide a strong rationale for a rapamycin-based therapeutic strategy.published_or_final_versio

Cost-Effectiveness of “Golden Mustard” for Treating Vitamin A Deficiency in India

BACKGROUND: Vitamin A deficiency (VAD) is an important nutritional problem in India, resulting in an increased risk of severe morbidity and mortality. Periodic, high-dose vitamin A supplementation is the WHO-recommended method to prevent VAD, since a single dose can compensate for reduced dietary intake or increased need over a period of several months. However, in India only 34 percent of targeted children currently receive the two doses per year, and new strategies are urgently needed. METHODOLOGY: Recent advancements in biotechnology permit alternative strategies for increasing the vitamin A content of common foods. Mustard (Brassica juncea), which is consumed widely in the form of oil by VAD populations, can be genetically modified to express high levels of beta-carotene, a precursor to vitamin A. Using estimates for consumption, we compare predicted costs and benefits of genetically modified (GM) fortification of mustard seed with high-dose vitamin A supplementation and industrial fortification of mustard oil during processing to alleviate VAD by calculating the avertable health burden in terms of disability-adjusted life years (DALY). PRINCIPAL FINDINGS: We found that all three interventions potentially avert significant numbers of DALYs and deaths. Expanding vitamin A supplementation to all areas was the least costly intervention, at $23-$50 per DALY averted and $1,000-$6,100 per death averted, though cost-effectiveness varied with prevailing health subcenter coverage. GM fortification could avert 5 million-6 million more DALYs and 8,000-46,000 more deaths, mainly because it would benefit the entire population and not just children. However, the costs associated with GM fortification were nearly five times those of supplementation. Industrial fortification was dominated by both GM fortification and supplementation. The cost-effectiveness ratio of each intervention decreased with the prevalence of VAD and was sensitive to the efficacy rate of averted mortality. CONCLUSIONS: Although supplementation is the least costly intervention, our findings also indicate that GM fortification could reduce the VAD disease burden to a substantially greater degree because of its wider reach. Given the difficulties in expanding supplementation to areas without health subcenters, GM fortification of mustard seed is an attractive alternative, and further exploration of this technology is warranted

Report of the Topical Group on Higgs Physics for Snowmass 2021: The Case for Precision Higgs Physics

A future Higgs Factory will provide improved precision on measurements of Higgs couplings beyond those obtained by the LHC, and will enable a broad range of investigations across the fields of fundamental physics, including the mechanism of electroweak symmetry breaking, the origin of the masses and mixing of fundamental particles, the predominance of matter over antimatter, and the nature of dark matter. Future colliders will measure Higgs couplings to a few per cent, giving a window to beyond the Standard Model (BSM) physics in the 1-10 TeV range. In addition, they will make precise measurements of the Higgs width, and characterize the Higgs self-coupling. This report details the work of the EF01 and EF02 working groups for the Snowmass 2021 study.Comment: 44 pages, 40 figures, Report of the Topical Group on Higgs Physics for Snowmass 2021. The first four authors are the Conveners, with Contributions from the other author

Venous occlusion plethysmography and Doppler ultrasound in the assessment of the dynamic response of blood flow at the onset of exercise in the lower limb

Quantification of the dynamic characteristics of muscle blood flow during exercise can reveal a significant amount about the physiological state, which cannot be measured under resting conditions. Venous occlusion plethysmography (VOP) is a non-invasive blood flow measurement technique suitable to measuring whole limb blood flow, however, conflicting evidence exits pertaining to its accuracy in an exercise setting. The aim of this study was to test the validity of VOP against the more established blood flow measurement technique of Doppler ultrasound (DU) to quantify the dynamic response of leg blood flow (LBF) during exercise. Ten healthy young male participants performed 6 bouts of 6 min intermittent (3-s duty cycle: 1-s contraction, 2-s relaxation) plantar-flexion exercise of the right calf muscle in the prone position on a custom-built calf ergometer at 30, 50 and 70% of maximum voluntary contractions (MVC). Simultaneous VOP and DU measurements of LBF were recorded and repeated on two separate days so that in total, 4 bouts were performed at 30 and 50% MVC and 2 bouts at 70% MVC. Two empirical models (triphasic or quadraphasic)1 were fitted to averaged LBF data of all the individual time series of LBF using a weighted least-squares non-linear regression procedure2. A quadraphasic model was fitted in participants in whom a second or slow ‘decay' in blood flow was apparent (50% of the cases), but only the first and second ‘growth' phases and the first ‘decay' phase (which followed the first growth phase and was apparent in most cases) were compared across measurement techniques. Responses (shown as means ± SD) were compared using a Student's T-test or Wilcoxon Signed Rank test. The time constants (s) of the second growth phase of the LBF kinetic response were not different between measurement techniques (30% MVC: 20.4 ± 10.5 vs. 27.2 ± 19.7, 50% MVC: 19.0 ± 11.9 vs. 16.1 ± 7.3, 70% MVC: 9.1 ± 4.9 vs. 11.0 ± 3.9). Similarly, the end-amplitudes (mL.min-1) at 30 and 50% MVC were not different between VOP and DU (30% MVC: 353 ± 109 vs. 359 ± 95; 50% MVC: 535 ± 171 vs. 588 ± 182) but they were significantly lower for VOP than DU at 70% MVC (667 ± 230 vs. 798 ± 261). In addition, resting LBF estimates were also significantly lower for VOP than DU. The rest of the kinetic parameters were not affected by measuring technique. The current study supports the validity of using VOP as an accurate technique to measure the dynamic response of lower limb blood flow during exercise. However, VOP tends to underestimate the total amplitude of the LBF response at high intensities (i.e. 70% MVC) most likely given that arterial inflow into the limb is progressively reduced as the venous volume and pressure rises, with the possibility of venous outflow.

Venous occlusion plethysmography and Doppler ultrasound in the assessment of the dynamic response of blood flow at the onset of exercise in the lower limb

Quantification of the dynamic characteristics of muscle blood flow during exercise can reveal a significant amount about the physiological state, which cannot be measured under resting conditions. Venous occlusion plethysmography (VOP) is a non-invasive blood flow measurement technique suitable to measuring whole limb blood flow, however, conflicting evidence exits pertaining to its accuracy in an exercise setting. The aim of this study was to test the validity of VOP against the more established blood flow measurement technique of Doppler ultrasound (DU) to quantify the dynamic response of leg blood flow (LBF) during exercise. Ten healthy young male participants performed 6 bouts of 6 min intermittent (3-s duty cycle: 1-s contraction, 2-s relaxation) plantar-flexion exercise of the right calf muscle in the prone position on a custom-built calf ergometer at 30, 50 and 70% of maximum voluntary contractions (MVC). Simultaneous VOP and DU measurements of LBF were recorded and repeated on two separate days so that in total, 4 bouts were performed at 30 and 50% MVC and 2 bouts at 70% MVC. Two empirical models (triphasic or quadraphasic)1 were fitted to averaged LBF data of all the individual time series of LBF using a weighted least-squares non-linear regression procedure2. A quadraphasic model was fitted in participants in whom a second or slow ‘decay' in blood flow was apparent (50% of the cases), but only the first and second ‘growth' phases and the first ‘decay' phase (which followed the first growth phase and was apparent in most cases) were compared across measurement techniques. Responses (shown as means ± SD) were compared using a Student's T-test or Wilcoxon Signed Rank test. The time constants (s) of the second growth phase of the LBF kinetic response were not different between measurement techniques (30% MVC: 20.4 ± 10.5 vs. 27.2 ± 19.7, 50% MVC: 19.0 ± 11.9 vs. 16.1 ± 7.3, 70% MVC: 9.1 ± 4.9 vs. 11.0 ± 3.9). Similarly, the end-amplitudes (mL.min-1) at 30 and 50% MVC were not different between VOP and DU (30% MVC: 353 ± 109 vs. 359 ± 95; 50% MVC: 535 ± 171 vs. 588 ± 182) but they were significantly lower for VOP than DU at 70% MVC (667 ± 230 vs. 798 ± 261). In addition, resting LBF estimates were also significantly lower for VOP than DU. The rest of the kinetic parameters were not affected by measuring technique. The current study supports the validity of using VOP as an accurate technique to measure the dynamic response of lower limb blood flow during exercise. However, VOP tends to underestimate the total amplitude of the LBF response at high intensities (i.e. 70% MVC) most likely given that arterial inflow into the limb is progressively reduced as the venous volume and pressure rises, with the possibility of venous outflow.