Miracle-dz/UniFAR-FTUs huggingface dataset:
Molecular reprogramming and phenotype switching in Staphylococcus aureus lead to high antibiotic persistence and affect therapy success

Significance Persisters represent a bacterial subpopulation that survive high antibiotic concentrations without being resistant. Their role in clinics in persistent infections and their molecular and functional landscape is not fully established. Staphylococcus aureus is a pathobiont that causes severe invasive infections often difficult to treat. Here, we assessed S. aureus recovered directly from persistent infections and show that host-mediated stress and antibiotic exposure promoted persister formation. Using a multiomics approach and enrichment of persisters, we were able to draw a molecular atlas of persisters, to correlate accumulation of insoluble proteins and ATP depletion with dormancy and persistence. Our results give insights into the molecular profile of bacterial persisters and provide a guide for therapy optimization for persistent S. aureus infections. Staphylococcus aureus causes invasive infections and easily acquires antibiotic resistance. Even antibiotic-susceptible S. aureus can survive antibiotic therapy and persist, requiring prolonged treatment and surgical interventions. These so-called persisters display an arrested-growth phenotype, tolerate high antibiotic concentrations, and are associated with chronic and recurrent infections. To characterize these persisters, we assessed S. aureus recovered directly from a patient suffering from a persistent infection. We show that host-mediated stress, including acidic pH, abscess environment, and antibiotic exposure promoted persister formation in vitro and in vivo. Multiomics analysis identified molecular changes in S. aureus in response to acid stress leading to an overall virulent population. However, further analysis of a persister-enriched population revealed major molecular reprogramming in persisters, including down-regulation of virulence and cell division and up-regulation of ribosomal proteins, nucleotide-, and amino acid-metabolic pathways, suggesting their requirement to fuel and maintain the persister phenotype and highlighting that persisters are not completely metabolically inactive. Additionally, decreased aconitase activity and ATP levels and accumulation of insoluble proteins involved in transcription, translation, and energy production correlated with persistence in S. aureus, underpinning the molecular mechanisms that drive the persister phenotype. Upon regrowth, these persisters regained their virulence potential and metabolically active phenotype, including reduction of insoluble proteins, exhibiting a reversible state, crucial for recurrent infections. We further show that a targeted antipersister combination therapy using retinoid derivatives and antibiotics significantly reduced lag-phase heterogeneity and persisters in a murine infection model. Our results provide molecular insights into persisters and help explain why persistent S. aureus infections are so difficult to treat.
A voltage-dependent Ca2+ -homeostat operates in the plant vacuolar membrane.

Cytosolic calcium signals are evoked by a large variety of biotic and abiotic stimuli and play an important role in cellular and long distance signaling in plants. While the function of the plasma membrane in cytosolic Ca2+ signaling has been intensively studied, the role of the vacuolar membrane remains elusive. A newly developed vacuolar voltage-clamp technique was used in combination with live-cell imaging, to study the role of the vacuolar membrane in Ca2+ and pH homeostasis of bulging root hair cells of Arabidopsis. Depolarization of the vacuolar membrane caused a rapid increase of the Ca2+ concentration and alkalized the cytosol, while hyperpolarization led to the opposite responses. The relationship between the vacuolar membrane potential, the cytosolic pH and Ca2+ concentration suggests that a vacuolar H+ /Ca2+ exchange mechanism plays a central role in cytosolic Ca2+ homeostasis. Mathematical modelling further suggests that the voltage-dependent vacuolar Ca2+ homeostat could contribute to calcium signaling when coupled to a recently discovered K+ channel-dependent module for electrical excitability of the vacuolar membrane.
Variations of Serum Oxidative Stress Biomarkers under First-Line Antituberculosis Treatment: A Pilot Study

Tuberculosis (TB) is one of the highest infectious burdens worldwide, and pathogenesis is yet incompletely elucidated. Bacilli dissemination is due to poor antioxidant defense mechanisms and intensified oxidative stress. There are few recent studies that analyzed and compared free radicals or antioxidant status before and after anti-TB treatment. Hence, the present study underlines the need to identify oxidative stress as it could be a useful tool in TB monitorisation. Thirty newly diagnosed patients with pulmonary TB were included after signing an informed consent. Blood was collected before receiving first-line anti-tubercular therapy (T0) and after 60 days (T2). Spectrophotometric methods were used to quantify oxidative parameters (TBARS—thiobarbituric acid reactive species); enzymatic antioxidants such as SOD (superoxide dismutase), CAT (catalase), GPx (glutathione peroxidase), and TAC (total antioxidant capacity); and non-enzymatic antioxidants such as GSH (reduced glutathione). A moderate positive correlation was found between GSH and TAC (r = 0.63, p-value = 0.046) and GSH and SOD (r = 0.64, p-value = 0.041) at T2. Increased values of GSH, CAT, and SOD were noted at T2 in comparison with T0, while GPx, TAC, and TBARS decreased at T2. A better monitorisation in TB could be based on oxidative stress and antioxidant status. Nevertheless, restoring redox host balance could reduce TB progression.
Effect of Soybean Oil Supplementation on Milk Production, Digestibility, and Metabolism in Dairy Goats under Thermoneutral and Heat Stress Conditions

Simple Summary Heat stress (HS) not only reduces milk yield but also depresses its contents of fat and protein, which might negatively impact cheese making. Dietary supplementation with soybean oil (SBO) could increase milk fat and improve milk fatty acid (FA) profiles in dairy goats. In the present study dairy goats were exposed to thermoneutral (TN; 15 to 20 °C) or HS (12 h/d at 37 °C and 12 h/d at 30 °C) conditions. In each ambient temperature, goats were fed a control diet (CON) or the same diet supplemented with SBO. Goats in HS suffered depressed feed intake and milk production, but they had greater digestibility coefficients compared to TN goats. Regardless of the HS treatment, goats supplemented with SBO produced milk with greater contents of fat, monounsaturated FA, and conjugated linoleic acid, without any negative effects on milk protein content. In conclusion, dietary supplementation with soybean oil was a useful strategy to increase milk fat and improve its fatty acid profile. Both TN and HS goats responded to soybean oil supplementation similarly since the interaction between soybean oil supplementation and temperature treatment was not significant. Abstract In a previous work, we observed that heat-stressed goats suffer reductions in milk yield and its contents of fat and protein. Supplementation with soybean oil (SBO) may be a useful strategy to enhance milk quality. In total, eight multiparous Murciano–Granadina dairy goats (42.8 ± 1.3 kg body weight; 99 ± 1 days of lactation) were used in a replicated 4 × 4 Latin square design with four periods; 21 d each (14 d adaptation, 5 d for measurements and 2 d transition between periods). Goats were allocated to one of four treatments in a 2 × 2 factorial arrangement. Factors were no oil (CON) or 4% of soybean oil (SBO), and controlled thermal neutral (TN; 15 to 20 °C) or heat stress (HS; 12 h/d at 37 °C and 12 h/d at 30 °C) conditions. This resulted in four treatment combinations: TN-CON, TN-SBO, HS-CON, and HS-SBO. Compared to TN, HS goats experienced lower (p < 0.05) feed intake, body weight, N retention, milk yield, and milk protein and lactose contents. However, goats in HS conditions had greater (p < 0.05) digestibility coefficients (+5.1, +5.2, +4.6, +7.0, and +8.9 points for dry matter, organic matter, crude protein, neutral detergent fiber, and acid detergent fiber, respectively) than TN goats. The response to SBO had the same magnitude in TN and HS conditions. Supplementation with SBO had no effects on feed intake, milk yield, or milk protein content. However, SBO supplementation increased (p < 0.05) blood non-esterified fatty acids by 50%, milk fat by 29%, and conjugated linoleic acid by 360%. In conclusion, feeding 4% SBO to dairy goats was a useful strategy to increase milk fat and conjugated linoleic acid without any negative effects on intake, milk yield, or milk protein content. These beneficial effects were obtained regardless goats were in TN or HS conditions.
Combinations of Radiotherapy with Vaccination and Immune Checkpoint Inhibition Differently Affect Primary and Abscopal Tumor Growth and the Tumor Microenvironment

Simple Summary Radiotherapy (RT) with higher single doses is capable of creating a beneficial immunological tumor microenvironment for additional immune therapies to trigger systemic anti-tumor immune responses. Here, we aimed to boost RT-induced immune responses with inactivated whole tumor cell vaccines generated with high hydrostatic pressure (HHP) and to break immunosuppression by inhibition of suppressive immune checkpoint molecules, such as PD-1. Our results highlight that HHP vaccines act systemically to retard tumor growth, but only of previously irradiated tumors. In contrast, abscopal anti-tumor immune responses, namely those to non-irradiated tumors, are triggered by a combination of RT of not too many fractions plus anti-PD-1, being characterized by the induction of distinct immune alterations in the primary and abscopal tumor, respectively. This emphasizes that future multimodal radioimmunotherapy approaches need to be carefully optimized regarding RT fractionation and the interaction of different immunotherapies with each other. Abstract Radiotherapy (RT) is known to have immune-modulatory properties. We hypothesized that RT and inactivated whole tumor cell vaccines generated with high hydrostatic pressure (HHP) synergize to retard the tumor growth which can be additionally improved with anti-PD-1 treatment. In abscopal tumor models, we injected mice with B16-F10 melanoma or TS/A mammary tumors. To evaluate the efficiency of RT in combination with HHP vaccines, we locally irradiated only one tumor with 2 × 8 Gy or 3 × 8 Gy. HHP vaccines further retarded the growth of locally irradiated (2 × 8 Gy) tumors. However, HHP vaccination combined with RT failed to induce abscopal anti-tumor immune responses, namely those to non-irradiated tumors, and even partly abrogated those which were induced with RT plus anti-PD-1. In the latter group, the abscopal effects were accompanied by an elevated infiltration of CD8+ T cells, monocytes/macrophages, and dendritic cells. 3 × 8 Gy failed to induce abscopal effects in association with increased expression of immunosuppressive checkpoint molecules compared to 2 × 8 Gy. We conclude that HHP vaccines induce anti-tumor effects, but only if the tumor microenvironment was previously modulated by hypofractionated RT with not too many fractions, but failed to improve RT plus anti-PD-induced abscopal responses that are characterized by distinct immune alterations.
Thermal performance of the Chagas disease vector, Triatoma infestans, under thermal variability

Vector-borne diseases (VBD) are particularly susceptible to climate change because most of the diseases’ vectors are ectotherms, which themselves are susceptible to thermal changes. The Chagas disease is one neglected tropical disease caused by the protozoan parasite, Trypanosoma cruzi. One of the main vectors of the Chagas disease in South America is Triatoma infestans, a species traditionally considered to be restricted to domestic or peridomestic habitats, but sylvatic foci have also been described along its distribution. The infestation of wild individuals, together with the projections of environmental changes due to global warming, urge the need to understand the relationship between temperature and the vector’s performance. Here, we evaluated the impact of temperature variability on the thermal response of T. infestans. We acclimated individuals to six thermal treatments for five weeks to then estimate their thermal performance curves (TPCs) by measuring the walking speed of the individuals. We found that the TPCs varied with thermal acclimation and body mass. Individuals acclimated to a low and variable ambient temperature (18°C ± 5°C) exhibited lower performances than those individuals acclimated to an optimal temperature (27°C ± 0°C); while those individuals acclimated to a low but constant temperature (18°C ± 0°C) did not differ in their maximal performance from those at an optimal temperature. Additionally, thermal variability (i.e., ± 5°C) at a high temperature (30°C) increased performance. These results evidenced the plastic response of T. infestans to thermal acclimation. This plastic response and the non-linear effect of thermal variability on the performance of T. infestans posit challenges when predicting changes in the vector’s distribution range under climate change.
Management of Lupus Nephritis

Lupus nephritis (LN) is a frequent and severe manifestation of systemic lupus erythematosus. The main goal of the management of LN is to avoid chronic kidney disease (CKD). Current treatment strategies remain unsatisfactory in terms of complete renal response, prevention of relapses, CKD, and progression to end-stage kidney disease. To improve the prognosis of LN, recent data suggest that we should (i) modify our treat-to-target approach by including, in addition to a clinical target, a pathological target and (ii) switch from conventional sequential therapy to combination therapy. Here, we also review the results of recent controlled randomized trials.
Phosphoproteomic Analysis as an Approach for Understanding Molecular Mechanisms of cAMP-Dependent Actions

In recent years, highly sensitive mass spectrometry–based phosphoproteomic analysis is beginning to be applied to identification of protein kinase substrates altered downstream of increased cAMP. Such studies identify a very large number of phosphorylation sites regulated in response to increased cAMP. Therefore, we now are tasked with the challenge of determining how many of these altered phosphorylation sites are relevant to regulation of function in the cell. This minireview describes the use of phosphoproteomic analysis to monitor the effects of cyclic nucleotide phosphodiesterase (PDE) inhibitors on cAMP-dependent phosphorylation events. More specifically, it describes two examples of this approach carried out in the authors’ laboratories using the selective PDE inhibitor approach. After a short discussion of several likely conclusions suggested by these analyses of cAMP function in steroid hormone–producing cells and also in T-cells, it expands into a discussion about some newer and more speculative interpretations of the data. These include the idea that multiple phosphorylation sites and not a single rate-limiting step likely regulate these and, by analogy, many other cAMP-dependent pathways. In addition, the idea that meaningful regulation requires a high stoichiometry of phosphorylation to be important is discussed and suggested to be untrue in many instances. These new interpretations have important implications for drug design, especially for targeting pathway agonists. SIGNIFICANCE STATEMENT Phosphoproteomic analyses identify thousands of altered phosphorylation sites upon drug treatment, providing many possible regulatory targets but also highlighting questions about which phosphosites are functionally important. These data imply that multistep processes are regulated by phosphorylation at not one but rather many sites. Most previous studies assumed a single step or very few rate-limiting steps were changed by phosphorylation. This concept should be changed. Previous interpretations also assumed substoichiometric phosphorylation was not of regulatory importance. This assumption also should be changed.
Disclosure of HIV status to sexual partners among perinatally HIV–infected youth in Thailand

Data regarding disclosure of HIV status to sexual partners among perinatally acquired HIV-infected (PHIV) youth are limited, particularly from Asian countries. This cross-sectional study assessed the patterns of, attitudes about, and factors associated with HIV disclosure to sexual partners among PHIV youth aged 15–24 years who attended a pediatric HIV clinic in Thailand. Participants were interviewed using a semi-structured questionnaire designed to elicit demographic and sexual behavior information. Those who had sexual partners were queried about their relationship and HIV status disclosure. Reasons to disclose or not to disclose were assessed accordingly. Among the 51 (44.4%) youth who had sexual partners, 55.8% had steady partners, 45.1% did not always use condoms, and 41.2% disclosed their HIV status. Reasons to disclose included trust and concern about the risk of infection to their partners. Reasons not to disclose included fear of rejection and stigmatization, and not knowing how to disclose. Most youth reported a need for disclosure-related guidance. Knowing their sexual partner’s HIV status was the only independent factor associated with disclosure (aOR 14.6; 95% CI 2.8–75.4). This study demonstrates a high rate of unsafe sex and a low rate of partner disclosure in PHIV youth, and highlights the need for a comprehensive guideline for HIV disclosure to sexual partners.
Recent advances in methanation catalysts for the production of synthetic natural gas

Methanation of coal-or biomass-derived carbon oxides for production of synthetic natural gas (SNG) is gaining considerable interest due to energy issues and the opportunity of reducing greenhouse gases by carbon dioxide conversion. The key component of the methanation process is the catalyst design. Ideally, the catalyst should show high activity at low temperatures (200-300 degrees C) and high stability at high temperatures (600-700 degrees C). In the past decades, various methanation catalysts have been investigated, among which transition metals including Ni, Fe, Co, Ru, Mo, etc. dispersed on metal oxide supports such as Al2O3, SiO2, TiO2, ZrO2, CeO2 etc. have received great attention due to their relatively high catalytic activity and selectivity. Furthermore, over the past few years, great efforts have been made both in methanation catalysts development and reaction mechanism investigation. Here we provide a comprehensive review to these most advancements, covering the reaction thermodynamics, mechanism and kinetics, the effects of catalyst active components, supports, promoters and preparation methods, hoping to outline the pathways for the future methanation catalysts design and development for SNG production.
Old Question Revisited: Are High-Protein Diets Safe in Pregnancy?

Background: A previous randomized dietary intervention in pregnant women from the 1970s, the Harlem Trial, reported retarded fetal growth and excesses of very early preterm births and neonatal deaths among those receiving high-protein supplementation. Due to ethical challenges, these findings have not been addressed in intervention settings. Exploring these findings in an observational setting requires large statistical power due to the low prevalence of these outcomes. The aim of this study was to investigate if the findings on high protein intake could be replicated in an observational setting by combining data from two large birth cohorts. Methods: Individual participant data on singleton pregnancies from the Danish National Birth Cohort (DNBC) (n = 60,141) and the Norwegian Mother, Father and Child Cohort Study (MoBa) (n = 66,302) were merged after a thorough harmonization process. Diet was recorded in mid-pregnancy and information on birth outcomes was extracted from national birth registries. Results: The prevalence of preterm delivery, low birth weight and fetal and neonatal deaths was 4.77%, 2.93%, 0.28% and 0.17%, respectively. Mean protein intake (standard deviation) was 89 g/day (23). Overall high protein intake (>100 g/day) was neither associated with low birth weight nor fetal or neonatal death. Mean birth weight was essentially unchanged at high protein intakes. A modest increased risk of preterm delivery [odds ratio (OR): 1.10 (95% confidence interval (CI): 1.01, 1.19)] was observed for high (>100 g/day) compared to moderate protein intake (80–90 g/day). This estimate was driven by late preterm deliveries (weeks 34 to <37) and greater risk was not observed at more extreme intakes. Very low (<60 g/day) compared to moderate protein intake was associated with higher risk of having low-birth weight infants [OR: 1.59 (95%CI: 1.25, 2.03)]. Conclusions: High protein intake was weakly associated with preterm delivery. Contrary to the results from the Harlem Trial, no indications of deleterious effects on fetal growth or perinatal mortality were observed.
Effect of high-pressure processing on moisture sorption properties of brown rice

ABSTRACT The effect of high-pressure treatment (0.1 to 500 MPa for 10 min) on the moisture sorption properties of brown rice (Feng Liang You Xiang No. 1) was investigated. Air was maintained at selected conditions (temperature between 20°C and 40°C, equilibrium relative humidity between 11% and 75%) and equilibrium moisture content was measured. The control attained a higher equilibrium moisture content than treated samples, while the 300 MPa treated sample had the lowest. The area of hysteresis of the 300 MPa test sample was the largest and the BET model was applied to determine the monolayer moisture content.
GEL CHROMATOGRAPHY OF HUMIC ACID

Summary Gel-solute interactions have been reported in the application of gel chromatography to humic acid. The origins and nature of these interactions are discussed with particular reference to the behaviour of ‘Sephadex’ with compounds which are aromatic, heterocyclic, phenolic, or charged. Such structural units are known to be present in humic acid and could account for its observed interactions with ‘Sephadex’gel. The behaviour of humic acid on ‘Sephadex’and a number of other gel materials in a variety of eluants is examined. The observed deviations of these systems from that of an ideal gel chromatography system are explained in terms of charge and adsorption effects. The results indicate that a fractionation based solely on molecular weight differences can be achieved by using an alkaline buffer containing a large ammo cation as eluant together with ‘Bio-gel’, ‘Sephadex’ or an agar based gel. Systems in which gel-solute interactions occur should not be used for molecular weight fractionations.
The Production of Artificial Soil Mix from Coal Fly Ash and Sewage Sludge

The scarcity of land in Hong Kong makes landfilling an unattractive means for the disposal of sewage sludge and coal fly ash. Therefore, reutilisation of these solid wastes might ease the disposal problems. A glasshouse pot leaching study was performed to evaluate the feasibility of using alkaline fly ash as a stabilisation agent for sewage sludge and the final product being used as a potting medium. Sludge was amended with ash at 0, 5, 10, 35 and 50% (w/w). Each mixture was then mixed with a loamy soil (1:1 v/v) and leached with 600 mL of deionized water prior to plant growth experiment using Agropyron elongatum (Tall wheat grass). Soil pH and electrical conductivity following leaching increased consistently with an increase in ash amendment, from 6.3 to 8.2 and 1.6 to 2.3 dS m−1 respectively. Pots amended with 35% ash showed a significant reduction in Zn, Cu and Cd availability but an increase in B contents. The total dry weight yields of ash amended pots were significantly increased as compared to the .