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Background Mesenchymal stem cells (MSCs) are promising for cell-based therapies targeting a wide range of diseases. However, challenges in translating MSC-based therapies to clinical applications necessitate standardized protocols following Good Manufacturing Practices (GMP) guidelines. This study aimed at developing GMP-complained protocols for FPMSCs isolation and manipulation, necessary for translational research, by (1) optimize culture of MSCs derived from an infrapatellar fat pad (FPMSC) condition through animal-free media comparison and (2) establish feasibility of MSC isolation, manufacturing and storage under GMP-compliance (GMP-FPMSC). Methods FPMSCs from three different patients were isolated following established protocols and the efficacy of two animal component-free media formulations in the culturing media were evaluated. The impact of different media formulations on cell proliferation, purity, and potency of MSCs was evaluated through doubling time, colony forming unit assay, and percentage of MSCs, respectively. Furthermore, the isolation and expansion of GMP-FPMSCs from four additional donors were optimized and characterized at each stage according to GMP requirements. Viability and sterility were checked using Trypan Blue and Bact/Alert, respectively, while purity and identity were confirmed using Endotoxin, Mycoplasma assays, and Flow Cytometry. The study also included stability assessments post-thaw and viability assessment to determine the shelf-life of the final GMP-FPMSC product. Statistical analyses were conducted using one-way ANOVA with Tukey’s Multiple Comparisons. Results The study demonstrated that FPMSCs exhibited enhanced proliferation rates when cultured in MSC-Brew GMP Medium compared to standard MSC media. Cells cultured in this media showed lower doubling times across passages, indicating increased proliferation. Additionally, higher colony formation in FPMSCs cultured in MSC-Brew GMP Medium were observed, supporting enhanced potency. Data from our GMP validation, including cells from 4 different donors, showed post-thaw GMP-FPMSC maintained stem cell marker expression and all the specifications required for product release, including > 95% viability (> 70% is required) and sterility, even after extended storage (up to 180 days), demonstrating the reproducibility and potential of GMP-FPMSCs for clinical use as well as the robustness of the isolation and storage protocols. Conclusions The study underscores the feasibility of FPMSCs for clinical uses under GMP conditions and emphasizes the importance of optimized culture protocols to improve cell proliferation and potency in MSC-based therapies.

Farmers’ markets aim to bring producers and consumers together under direct marketing schemes, also known as alternative food networks, for local and sustainable production and consumption of food. A number of studies concerning this subject have been published, however, as yet no updated reviews exist that might allow us to understand the trends in research on farmers’ markets. The objective of this study was to examine the farmers’ market literature using bibliometric tools. A total of 438 peer-reviewed publications, indexed in the abstract and citation meta-database Scopus (Elsevier®), for the period of 1979 to September 24, 2018, were considered. In the second phase, publications in the area of medicine were excluded, resulting in 295 publications being analyzed for the same period. The results showed that these publications focused on three main areas: markets, health programs, and food safety. Upon exclusion of the medical publications, the remaining works focused on farmers’ market actors, dynamics, and attributes: vendors (producers and others), consumers, the community, and supporting actors and institutions (government, NGOs, individuals). Therefore, it is concluded that there is no single type of farmers’ market, nor of farmers’ market vendors or consumers. This makes the reproduction of such spaces difficult, especially when the goals are to benefit local production systems or the nutrition of the local community.

Since the detection of the first case of COVID-19 in Chile on March 3 rd , 2020, a total of 513,188 cases, including ~14,302 deaths have been reported in Chile as of November 2 nd , 2020. Here, we estimate the reproduction number throughout the epidemic in Chile and study the effectiveness of control interventions especially the effectiveness of lockdowns by conducting short-term forecasts based on the early transmission dynamics of COVID-19. Chile’s incidence curve displays early sub-exponential growth dynamics with the deceleration of growth parameter, p , estimated at 0.8 (95% CI: 0.7, 0.8) and the reproduction number, R , estimated at 1.8 (95% CI: 1.6, 1.9). Our findings indicate that the control measures at the start of the epidemic significantly slowed down the spread of the virus. However, the relaxation of restrictions and spread of the virus in low-income neighborhoods in May led to a new surge of infections, followed by the reimposition of lockdowns in Greater Santiago and other municipalities. These measures have decelerated the virus spread with R estimated at ~0.96 (95% CI: 0.95, 0.98) as of November 2 nd , 2020. The early sub-exponential growth trend ( p ~0.8) of the COVID-19 epidemic transformed into a linear growth trend ( p ~0.5) as of July 7 th , 2020, after the reimposition of lockdowns. While the broad scale social distancing interventions have slowed the virus spread, the number of new COVID-19 cases continue to accrue, underscoring the need for persistent social distancing and active case detection and isolation efforts to maintain the epidemic under control.

Lactate has been shown to offer neuroprotection in several pathologic conditions. This beneficial effect has been attributed to its use as an alternative energy substrate. However, recent description of the expression of the HCA1 receptor for lactate in the central nervous system calls for reassessment of the mechanism by which lactate exerts its neuroprotective effects. Here, we show that HCA1 receptor expression is enhanced 24 hours after reperfusion in an middle cerebral artery occlusion stroke model, in the ischemic cortex. Interestingly, intravenous injection of L-lactate at reperfusion led to further enhancement of HCA1 receptor expression in the cortex and striatum. Using an in vitro oxygen-glucose deprivation model, we show that the HCA1 receptor agonist 3,5-dihydroxybenzoic acid reduces cell death. We also observed that D-lactate, a reputedly non-metabolizable substrate but partial HCA1 receptor agonist, also provided neuroprotection in both in vitro and in vivo ischemia models. Quite unexpectedly, we show D-lactate to be partly extracted and oxidized by the rodent brain. Finally, pyruvate offered neuroprotection in vitro whereas acetate was ineffective. Our data suggest that L- and D-lactate offer neuroprotection in ischemia most likely by acting as both an HCA1 receptor agonist for non-astrocytic (most likely neuronal) cells as well as an energy substrate.

Anthracnose caused by species of Colletotrichum can result in avocado pre and postharvest losses. This disease has been controlled with synthetic fungicides that produce toxicological risks, the development of resistant pathogens, and consumer demand for fungicide-free foods. Due to this concern, antagonistic yeasts can be used as a natural alternative to control anthracnose. This study aimed to isolate and identify yeast strains from avocado fruits with the potential to control this pathogen and to evaluate the action mechanisms of the most promising yeast. Twenty-three yeasts were isolated from the avocado fruit epicarp. Seven yeasts showed in vitro antagonistic activity with inhibition of mycelial growth from 60.1 to 87.2%, and inhibition of spore germination from 95.3 to 100%. Yamadazyma mexicana LPa14 exhibited the best antagonist activity with a severity reduction of 63.63% and incidence of 60%. It also showed the ability to survive in hostile conditions of low water activity and high temperature with 64.29 and 93.45% of viability at aw 0.96 and 0.98 at 38 °C, respectively. The mechanisms of action of Y. mexicana LPa14 included colonization in the wounds of avocado fruit, competition for nutrients, adherence to the hyphae and spores of the pathogen, biofilm formation, and production of volatile organic compounds (VOCs). The main VOCs identified were alcohols (isopentan-1-ol, ethanol, 2-phenylethanol, 2-methyl-1-butanol) and esters (ethyl acetate and isopentyl acetate). This study demonstrated that Y. mexicana LPa14 is a viable biocontrol candidate for C. gloeosporioides and could be used as a suitable alternative to control preharvest and postharvest anthracnose disease in avocado fruits.

Whole virus-based inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide have been critical to the COVID-19 pandemic response. Although these vaccines are protective against homologous coronavirus infection, the emergence of novel variants and the presence of large zoonotic reservoirs harboring novel heterologous coronaviruses provide significant opportunities for vaccine breakthrough, which raises the risk of adverse outcomes like vaccine-associated enhanced respiratory disease. Here, we use a female mouse model of coronavirus disease to evaluate inactivated vaccine performance against either homologous challenge with SARS-CoV-2 or heterologous challenge with a bat-derived coronavirus that represents a potential emerging disease threat. We show that inactivated SARS-CoV-2 vaccines adjuvanted with aluminum hydroxide can cause enhanced respiratory disease during heterologous infection, while use of an alternative adjuvant does not drive disease and promotes heterologous viral clearance. In this work, we highlight the impact of adjuvant selection on inactivated vaccine safety and efficacy against heterologous coronavirus infection. Here, Dillard and Taft-Benz et al. show in a female mouse model how different adjuvants affect inactivated vaccine-mediated protection against homologous SARS-CoV-2 and heterologous SARS-CoV-1-like coronaviruses. They find that an aluminum hydroxide-adjuvanted vaccine can increase risk of adverse outcomes during heterologous infection.

The excessive use of fertilizers in agriculture is mainly due to the recognized plant requirements for soluble phosphorus. This problem has limited the implementation of sustainable agriculture. A viable alternative is to use phosphate solubilizing soil microorganisms. This work aimed to isolate inorganic phosphorus-solubilizing bacteria from the soils of agroecosystems, to select and identify, based on sequencing and phylogenetic analysis of the 16S rRNA gene, the bacterium with the highest capacity for in vitro solubilization of inorganic phosphate. Additionally, we aimed to determine its primary phosphate solubilizing mechanisms and to evaluate its effect on Habanero pepper seedlings growth. A total of 21 bacterial strains were isolated by their activity on Pikovskaya agar. Of these, strain ITCB-09 exhibited the highest ability to solubilize inorganic phosphate (865.98 µg/mL) through the production of organic acids. This strain produced extracellular polymeric substances and siderophores that have ecological implications for phosphate solubilization. 16S rRNA gene sequence analysis revealed that strain ITCB-09 belongs to the genus Enterobacter. Enterobacter sp. ITCB-09, especially when immobilized in beads, had a positive effect on Capsicum chinense Jacq. seedling growth, indicating its potential as a biofertilizer.

The transcription factor PU.1 is a critical regulator of lineage fate in blood-forming hematopoietic stem cells (HSC). In response to pro-inflammatory signals, such as the cytokine IL-1β, PU.1 expression is increased in HSC and is associated with myeloid lineage expansion. To address potential functional heterogeneities arising in the phenotypic HSC compartment due to changes in PU.1 expression, here, we fractionated phenotypic HSC in mice using the SLAM surface marker code in conjunction with PU.1 expression levels, using the PU.1-EYFP reporter mouse strain. While PU.1lo SLAM cells contain extensive long-term repopulating activity and a molecular signature corresponding to HSC activity at steady state, following IL-1β treatment, HSCLT induce PU.1 expression and are replaced in the PU.1lo SLAM fraction by CD41+ HSC-like megakaryocytic progenitors (SL-MkP) with limited long-term engraftment capacity. On the other hand, the PU.1hi SLAM fraction exhibits extensive myeloid lineage priming and clonogenic activity and expands rapidly in response to IL-1β. Furthermore, we show that EPCR expression, but not CD150 expression, can distinguish HSCLT and SL-MkP under inflammatory conditions. Altogether, our data provide insights into the dynamic regulation of PU.1 and identify how PU.1 levels are linked to HSC fate in steady state and inflammatory stress conditions.

Lipids, either endogenously synthesized or exogenous, have been linked to human cancer. Here we found that PML is frequently co-deleted with PTEN in metastatic human prostate cancer (CaP). We demonstrated that conditional inactivation of Pml in the mouse prostate morphs indolent Pten -null tumors into lethal metastatic disease. We identified MAPK reactivation, subsequent hyperactivation of an aberrant SREBP prometastatic lipogenic program, and a distinctive lipidomic profile as key characteristic features of metastatic Pml and Pten double-null CaP. Furthermore, targeting SREBP in vivo by fatostatin blocked both tumor growth and distant metastasis. Importantly, a high-fat diet (HFD) induced lipid accumulation in prostate tumors and was sufficient to drive metastasis in a nonmetastatic Pten -null mouse model of CaP, and an SREBP signature was highly enriched in metastatic human CaP. Thus, our findings uncover a prometastatic lipogenic program and lend direct genetic and experimental support to the notion that a Western HFD can promote metastasis. This study shows that inactivation of Pml in the mouse prostate turns indolent Pten -null tumors into lethal metastatic disease. The authors identify an aberrant SREBP prometastatic lipogenic program and show that a high-fat diet induces lipid accumulation in prostate tumors and is sufficient to drive metastasis.

Objective: The objective of the article is to showcase the utilisation of open innovation in new technology- based firms (NTBFs) from the perspective of entrepreneurs who have successfully survived the crossing of the valley of death. We examined the interplay of open innovation (OI), and the entrepreneurial background (i.e. human capital, entrepreneurial education) to identify success factors in crossing the valley of death. Research Design Methods: The research was qualitative and based on interviews conducted with founders of ten start-ups based in Madrid, Spain. To process the information obtained in a more objective manner, we utilised three R codes for qualitative data analysis. Subsequently, we employed word clouds to condense the interviews and ascertain the most significant variables related to the success of the ventures and OI. Findings: There were several recurring components among the entrepreneurs that have enabled them to suc- cessfully cross the valley of death. During the early stages, the entrepreneurship background becomes appar- ent, enabling them to implement their ideas based on the experience and knowledge acquired. In the subse- quent stage, the emergence of family support for entrepreneurship facilitates access to initial financing be- yond one’s own savings invested. Therefore, it appears that human capital and access to informal sources of finance are more critical for entrepreneurial success than open innovation.Implications Recommendations: Despite the fact that open innovation facilitates the acquisition of new knowledge from a theoretical standpoint, our results suggest that prioritising entrepreneurs’ human cap- ital and ensuring access to financing are more crucial in overcoming the valley of death, by optimizing the efforts of various stakeholders.Contribution Value Added: The article offers a comprehensive understanding of the survival process of non- traditional business enterprises (NTBFs) and categorises three distinct variables that contribute to compre- hending the significance of external and internal factors to which entrepreneurs are exposed.