Microbiota-Derived Short-Chain Fatty Acids: New Road in Colorectal Cancer Therapy

Copyright © 2022 by the authors. The colon microbiota is an important player in colorectal cancer (CRC) development, which is responsible for most of the cancer-related deaths worldwide. During carcinogenesis, the colon microbiota composition changes from a normobiosis profile to dysbiosis, interfering with the production of short-chain fatty acids (SCFAs). Each SCFA is known to play a role in several biological processes but, despite their reported individual effects, colon cells are exposed to these compounds simultaneously and the combined effect of SCFAs in colon cells is still unknown. Our aim was to explore the effects of SCFAs, alone or in combination, unveiling their biological impact on CRC cell phenotypes. We used a mathematical model for the prediction of the expected SCFA mixture effects and found that, when in mixture, SCFAs exhibit a concentration addition behavior. All SCFAs, alone or combined at the physiological proportions founded in the human colon, revealed to have a selective and anticancer effect by inhibiting colony formation and cell proliferation, increasing apoptosis, disturbing the energetic metabolism, inducing lysosomal membrane permeabilization, and decreasing cytosolic pH. We showed for the first time that SCFAs are specific towards colon cancer cells, showing promising therapeutic effects. These findings open a new road for the development of alternatives for CRC therapy based on the increase in SCFA levels through the modulation of the colon microbiota composition.EcoAgriFood (NORTE-01-0145-FEDER-00009), supported by Norte Portugal Regional Operational Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). Sara Gomes thanks the FCT for her PhD grant (SFRH/BD/140965/2018). This work was financed by the Portuguese Foundation for Science and Technology (Fundação para a Ciência e a Tecnologia, FCT) within the scope of project PTDC/QUIQIN/28662/2017. This work was also supported by the strategic programme UID/BIA/04050/2019, funded by national funds through the FCT I.P

Polycrystalline Ni nanotubes under compression: a molecular dynamics study

Mechanical properties of nanomaterials, such as nanowires and nanotubes, are an important feature for the design of novel electromechanical nano-architectures. Since grain boundary structures and surface modifications can be used as a route to modify nanostructured materials, it is of interest to understand how they affect material strength and plasticity. We report large-scale atomistic simulations to determine the mechanical response of nickel nanowires and nanotubes subject to uniaxial compression. Our results suggest that the incorporation of nanocrystalline structure allows completely flexible deformation, in sharp contrast with single crystals. While crystalline structures at high compression are dominated by dislocation pinning and the multiplication of highly localized shear regions, in nanocrystalline systems the dislocation distribution is significantly more homogeneous. Therefore, for large compressions (large strains) coiling instead of bulging is the dominant deformation mode. Additionally, it is observed that nanotubes with only 70% of the nanowire mass but of the same diameter, exhibit similar mechanical behavior up to 0.3 strain. Our results are useful for the design of new flexible and light-weight metamaterials, when highly deformable struts are required.Fil: Rojas Nunez, J.. Universidad de Santiago de Chile; ChileFil: Baltazar, S. E.. Universidad de Santiago de Chile; ChileFil: Gonzalez, R. I.. Universidad Mayor; ChileFil: Bringa, Eduardo Marcial. Universidad Mayor; Chile. Universidad de Mendoza. Facultad de Ingeniería; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Allende, S.. Universidad de Santiago de Chile; ChileFil: Kiwi, M.. Universidad de Santiago de Chile; ChileFil: Valencia, F. J.. Universidad de Santiago de Chile; Chile. Universidad Mayor; Chil

Monitoring and Verification Procedures Used in the Texas LoanSTAR and Rebuild America Programs

The monitoring and verification procedures that have been developed for the Texas LoanSTAR program and the ESL's Rebuild America Program have become a foundation for a number of other state and federal M&V programs, including the United States Department of Energy's (USDOE's) 1996 NEMVP, 1997 IPMVP, 2001 IPMVP, ASHRAE's GP 14P, and the 1999 Texas Performance Contracting Guidelines. This paper reviews the basic procedures that are used for monitoring and verifying energy savings in commercial buildings that receive energy conservation retrofits, including procedures that are used for measuring energy savings in buildings where hourly pre-retrofit and post-retrofit whole-building data have been collected; buildings where monthly pre-retrofit and hourly post-retrofit data are collected; and buildings where monthly preretrofit and monthly post-retrofit data are used to verify savings

Energy Efficiency/Renewable Energy Impact in the Texas Emissions Reduction Plan (TERP)

This report is a summary of the renewable energy projects installed throughout Texas after the year 2000. The collection of these projects was done in response to the Energy System Laboratory’s requirement to fulfill its obligations for Senate Bill 5 (SB5). The renewable energy projects researched and presented herein include: solar photovoltaic, solar thermal, hydroelectric, geothermal, and landfill gas-fired power plants. However, information on wind energy farms has been omitted in this report due to the fact that a more complete ESL report on this subject has already been prepared, ESL-TR-06-08-01. In addition to locating these projects, SB5 required the calculation of reduced NOx emissions. To accomplish this, the Energy Systems Laboratory (ESL) at Texas A&M University developed “eCalc” in 2004 -- a web-based Emissions Reduction Calculator. This program is able to calculate weather-normalized NOx emissions estimates for energy efficiency and renewable sources projects, such as solar photovoltaic, solar thermal, and wind. Annual energy savings from renewable projects resulted in the following: • Solar photovoltaic projects resulted in energy savings of 424.18 MWh/yr and a reduction of 0.28 tons of NOx/year. • Solar thermal projects resulted in energy savings of 332.88 MWh/yr and a reduction of 0.26 tons of NOx/year. The peak ozone season day (OSD) NOx reductions were calculated to be: • Solar photovoltaic projects resulted in savings of 1.29 MWh/day. • Solar thermal projects resulted in savings equivalent to 0.94 MWh/day. The emissions reduction values for hydroelectric and geothermal projects are not presented here since there is no methodology in place at this time to obtain these values

Estudo Qualitativo sobre a "Proposta de Ferramenta de Avaliação Qualitativa de Ementas destinadas a Idosos"- Qual a perceção e contributos dos nutricionistas para uma proposta de atualização?

As contínuas alterações demográficas colocam-nos perante uma população cada vez mais envelhecida e com necessidades crescentes de cuidados alimentares, tanto numa ótica de cuidados de saúde, como de fornecimento de refeições, necessidade frequentemente suprida por serviços de alimentação coletiva. A qualidade nutricional e alimentar da oferta assume-se como um determinante major na saúde e satisfação dos idosos, sendo o plano de ementas uma das mais importantes ferramentas de gestão na área. Para que seja promovida uma oferta alimentar adequada, é essencial a existência de orientações que a balizem e que sejam alvo de atualização e melhoria contínua. A envolvência de nutricionistas no processo possibilita a revisão por pares e uma maior adaptação à realidade, permitindo obter ferramentas que auxiliem na tomada de decisão e na sustentação do trabalho desenvolvido. O presente estudo tem como objetivo explorar a perceção e os contributos de nutricionistas sobre o documento “Proposta de Ferramenta de Avaliação Qualitativa de Ementas destinadas a Idosos”, visando uma proposta de atualização. Foi adotada uma metodologia qualitativa através da realização de grupos focais a partir de uma amostra por conveniência, constituída por 38 nutricionistas. Os resultados sugerem que, apesar de ser considerada útil, a ferramenta carece de atualização para uma maior adaptação à faixa etária e à realidade prática. Da análise de critérios específicos, os participantes identificam vários de difícil cumprimento (ex. oferta equitativa de métodos de confeção, não repetição de fruta, oferta de oleaginosas, refeições de ovo e de massa ou arroz integral), partilhando os motivos para tal. Sugerem ainda a necessidade de inclusão de critérios para alimentação de textura modificada e refletem acerca de possíveis melhorias na própria dinâmica de aplicação da ferramenta. Em suma, a discussão promovida deixa importantes contributos para uma possível atualização da ferramenta, numa ótica de maior ajuste à faixa etária e de inclusão de critérios sobre tópicos emergentes.Continuous demographic changes confront us with an increasingly elderly population with growing needs for nutritional care, both from a health care perspective and from meals’ provision, which is often supplied by food services. The nutritional and food quality is a major determinant of the seniors’ health and satisfaction, and the menu is one of the most important management tools. To promote an adequate food offer, it is essential to have guidelines, that must be updated and continuously improved. The involvement of nutritionists in this process enables peer review and greater adaptation to reality, allowing to obtain tools that help in the decision-making process and sustain the developed work. This work aims to explore the perceptions and contributions of nutritionists on the document “Proposta de Ferramenta de Avaliação Qualitativa de Ementas destinadas a Idosos”, with a view to an update proposal. A qualitative methodology was adopted by conducting focus groups with a convenience sample of 38 nutritionists. Results suggest that, although the tool is considered useful, it needs to be updated to better adapt to the targeted age group and to the practical context. From the analysis of specific criteria, participants identify difficulties to comply with some of them (e.g. equitable offering of cooking methods, non-repetition of fruit, offering of oilseeds, egg based meals and whole wheat pasta or wholegrain rice), sharing the reasons why. They also suggest the need to include criteria for texture modified foods and they reflect on possible improvements in the tool application. In conclusion, the discussion promoted breeds important contributions for a possible update of the tool, in a perspective of greater adjustment to the age group it is destined to and inclusion of criteria on emerging topics.info:eu-repo/semantics/publishedVersio

Quantifying neutralising antibody responses against SARS-CoV-2 in dried blood spots (DBS) and paired sera

The ongoing SARS-CoV-2 pandemic was initially managed by non-pharmaceutical interventions such as diagnostic testing, isolation of positive cases, physical distancing and lockdowns. The advent of vaccines has provided crucial protection against SARS-CoV-2. Neutralising antibody (nAb) responses are a key correlate of protection, and therefore measuring nAb responses is essential for monitoring vaccine efficacy. Fingerstick dried blood spots (DBS) are ideal for use in large-scale sero-surveillance because they are inexpensive, offer the option of self-collection and can be transported and stored at ambient temperatures. Such advantages also make DBS appealing to use in resource-limited settings and in potential future pandemics. In this study, nAb responses in sera, venous blood and fingerstick blood stored on filter paper were measured. Samples were collected from SARS-CoV-2 acutely infected individuals, SARS-CoV-2 convalescent individuals and SARS-CoV-2 vaccinated individuals. Good agreement was observed between the nAb responses measured in eluted DBS and paired sera. Stability of nAb responses was also observed in sera stored on filter paper at room temperature for 28 days. Overall, this study provides support for the use of filter paper as a viable sample collection method to study nAb responses

Baseline Report for the Fort Hood Army Base: Sept. 1, 2001 To Aug. 31, 2002

This report presents electricity, natural gas and cooling baselines for the thermal plant, buildings located in the 87000 block, and the III Corp building at Ft. Hood. A baseline analysis is also presented for the natural gas consumption for the Ft. Hood Army base. The baselines developed for this report include data measured during 2001/2002 for the thermal plant, 87000 block buildings, and III Corp building and natural gas data recorded over a several year period. Baseline analyses are presented for individual channels and groups of channels that represent loads determined to be of value to Ft. Hood. Preliminary baselines are also presented on new buildings for which manual data were provided for 2002. However, additional data collection is recommended for these buildings before accurate baseline can be developed. This report is divided into different sections that correspond to the different baseline analysis that were performed on the measured loads, including: an analysis of the chiller performance, an analysis of the weather-dependent channels at the thermal plant, baseline models for the 87000 block manual readings, III Corp building, and a whole-base natural gas baseline analysis. A description of the analysis methods is provided in the introduction. Additional details that pertain to the data that were collected are provided in each section. An appendix is also provided that includes information about the data logger parameter sets, and the daily data recorded manually for the 87000 block buildings, and daily data recorded manually for the new buildings

Development of Load Forecasting Procedures for the Texas A&M University System

This paper reports on the effort to develop load-forecasting procedures for the Texas A&M University System (TAMUS). Such procedures are being investigated to determine if the TAMUS can benefit from the pending deregulation in the State of Texas. A description of the procedures used to aggregate and forecast the system-wide, 15-minute electric load is presented, including a summary of the forecast load for selected campuses, and individual campus-use statistics. Procedures are also presented that were used to impute missing energy and weather data, and forecast annual data from short-term data

Novel human liver-tropic AAV variants define transferable domains that markedly enhance the human tropism of AAV7 and AAV8

Recent clinical successes have intensified interest in using adeno-associated virus (AAV) vectors for therapeutic gene delivery. The liver is a key clinical target, given its critical physiological functions and involvement in a wide range of genetic diseases. Here, we report the bioengineering of a set of next-generation AAV vectors, named AAV-SYDs (where “SYD” stands for Sydney, Australia), with increased human hepato-tropism in a liver xenograft mouse model repopulated with primary human hepatocytes. We followed a two-step process that staggered directed evolution and domain-swapping approaches. Using DNA-family shuffling, we first mapped key AAV capsid regions responsible for efficient human hepatocyte transduction in vivo. Focusing on these regions, we next applied domain-swapping strategies to identify and study key capsid residues that enhance primary human hepatocyte uptake and transgene expression. Our findings underscore the potential of AAV-SYDs as liver gene therapy vectors and provide insights into the mechanism responsible for their enhanced transduction profile

Attenuation of Heparan Sulfate Proteoglycan Binding Enhances In Vivo Transduction of Human Primary Hepatocytes with AAV2

Use of the prototypical adeno-associated virus type 2 (AAV2) capsid delivered unexpectedly modest efficacy in an early liver-targeted gene therapy trial for hemophilia B. This result is consistent with subsequent data generated in chimeric mouse-human livers showing that the AAV2 capsid transduces primary human hepatocytes in vivo with low efficiency. In contrast, novel variants generated by directed evolution in the same model, such as AAV-NP59, transduce primary human hepatocytes with high efficiency. While these empirical data have immense translational implications, the mechanisms underpinning this enhanced AAV capsid transduction performance in primary human hepatocytes are yet to be fully elucidated. Remarkably, AAV-NP59 differs from the prototypical AAV2 capsid by only 11 aa and can serve as a tool to study the correlation between capsid sequence/structure and vector function. Using two orthogonal vectorological approaches, we have determined that just 2 of the 11 changes present in AAV-NP59 (T503A and N596D) account for the enhanced transduction performance of this capsid variant in primary human hepatocytes in vivo, an effect that we have associated with attenuation of heparan sulfate proteoglycan (HSPG) binding affinity. In support of this hypothesis, we have identified, using directed evolution, two additional single amino acid substitution AAV2 variants, N496D and N582S, which are highly functional in vivo. Both substitution mutations reduce AAV2's affinity for HSPG. Finally, we have modulated the ability of AAV8, a highly murine-hepatotropic serotype, to interact with HSPG. The results support our hypothesis that enhanced HSPG binding can negatively affect the in vivo function of otherwise strongly hepatotropic variants and that modulation of the interaction with HSPG is critical to ensure maximum efficiency in vivo. The insights gained through this study can have powerful implications for studies into AAV biology and capsid development for preclinical and clinical applications targeting liver and other organs