A comparative survey between cascade correlation neural network (CCNN) and feedforward neural network (FFNN) machine learning models for forecasting suspended sediment concentration.

Suspended sediment concentration prediction is critical for the design of reservoirs, dams, rivers ecosystems, various operations of aquatic resource structure, environmental safety, and water management. In this study, two different machine models, namely the cascade correlation neural network (CCNN) and feedforward neural network (FFNN) were applied to predict daily-suspended sediment concentration (SSC) at Simga and Jondhara stations in Sheonath basin, India. Daily-suspended sediment concentration and discharge data from 2010 to 2015 were collected and used to develop the model to predict suspended sediment concentration. The developed models were evaluated using statistical indices like Nash and Sutcliffe efficiency coefficient (NES), root mean square error (RMSE), Willmott's index of agreement (WI), and Legates-McCabe's index (LM), supplemented by a scatter plot, density plots, histograms and Taylor diagram for graphical representation. The developed model was evaluated and compared with CCNN and FFNN. Nine input combinations were explored using different lag-times for discharge (Qt-n) and suspended sediment concentration (St-n) as input variables, with the current suspended sediment concentration as the desired output, to develop CCNN and FFNN models. The CCNN4 model with 4 lagged inputs (St-1, St-2, St-3, St-4) outperformed the other developed models with the lowest RMSE = 95.02 mg/l and the highest NES = 0.0.662, WI = 0.890 and LM = 0.668 for the Jondhara Station while the same CCNN4 model secure as the best with the lowest RMSE = 53.71 mg/l and the highest NES = 0.785, WI = 0.936 and LM = 0.788 for the Simga Station. The result shows the CCNN model was better than the FFNN model for predicting daily-suspended sediment at both stations in the Sheonath basin, India. Overall, CCNN showed better forecasting potential for suspended sediment concentration compared to FFNN at both stations, demonstrating their applicability for hydrological forecasting with complex relationships.

Pharmacokinetic and Metabolomic Studies with a Promising Radiation Countermeasure, BBT-059 (PEGylated interleukin-11), in Rhesus Nonhuman Primates.

BBT-059, a long-acting PEGylated interleukin-11 (IL-11) analog that is believed to have hematopoietic promoting and anti-apoptotic properties, is being developed as a potential radiation medical countermeasure (MCM) for hematopoietic acute radiation syndrome (H-ARS). This agent has been shown to improve survival in lethally irradiated mice. To further evaluate the drug's toxicity and safety profile, 12 naïve nonhuman primates (NHPs, rhesus macaques) were administered one of three doses of BBT-059 subcutaneously and were monitored for the next 21 days. Blood samples were collected throughout the study to assess the pharmacokinetics (PK) and pharmacodynamics (PD) of the drug as well as its effects on complete blood counts, cytokines, vital signs, and to conduct metabolomic studies. No adverse effects were detected in any treatment group during the study. Short-term changes in metabolomic profiles were present in all groups treated with BBT-059 beginning immediately after drug administration and reverting to near normal levels by the end of the study period. Several pathways and metabolites, particularly those related to inflammation and steroid hormone biosynthesis, were activated by BBT-059 administration. Taken together, these observations suggest that BBT-059 has a good safety profile for further development as a radiation MCM for regulatory approval for human use.

Skeletal Muscle Mitochondrial Dysfunction Mediated by Pseudomonas aeruginosa Quorum Sensing Transcription Factor MvfR: Reversing Effects with Anti-MvfR and Mitochondrial-Targeted Compounds.

Sepsis and chronic infections with Pseudomonas aeruginosa, a leading "ESKAPE" bacterial pathogen, are associated with increased morbidity and mortality and skeletal muscle atrophy. The actions of this pathogen on skeletal muscle remain poorly understood. In skeletal muscle, mitochondria serve as a crucial energy source, which may be perturbed by infection. Here, using the well-established backburn and infection model of murine P. aeruginosa infection, we deciphered the systemic impact of the quorum sensing (QS) transcription factor MvfR by interrogating five days post-infection its effect on mitochondrial-related functions in the gastrocnemius skeletal muscle and the outcome of the pharmacological inhibition of MvfR function and that of the mitochondrial-targeted peptide, Szeto-Schiller 31 (SS-31). Our findings show that the MvfR perturbs ATP generation, oxidative phosphorylation (OXPHOS), and antioxidant response, elevates the production of reactive oxygen species, and promotes oxidative damage of mitochondrial DNA in the gastrocnemius muscle of infected mice. These impairments in mitochondrial-related functions were corroborated by the alteration of key mitochondrial proteins involved in electron transport, mitochondrial biogenesis, dynamics and quality control, and mitochondrial uncoupling. Pharmacological inhibition of MvfR using the potent anti-MvfR lead, D88, we developed, or the mitochondrial-targeted peptide SS-31 rescued the MvfR- mediated alterations observed in mice infected with the wild-type strain PA14. Our study provides insights into the actions of MvfR in orchestrating mitochondrial dysfunction in the skeletal murine muscle, and it presents novel therapeutic approaches for optimizing clinical outcomes in affected patients.

Silicon regulates phosphate deficiency through involvement of auxin and nitric oxide in barley roots.

MAIN CONCLUSION: Silicon application mitigates phosphate deficiency in barley through an interplay with auxin and nitric oxide, enhancing growth, photosynthesis, and redox balance, highlighting the potential of silicon as a fertilizer for overcoming nutritional stresses. Silicon (Si) is reported to attenuate nutritional stresses in plants, but studies on the effect of Si application to plants grown under phosphate (Pi) deficiency are still very scarce, especially in barley. Therefore, the present work was undertaken to investigate the potential role of Si in mitigating the adverse impacts of Pi deficiency in barley Hordeum vulgare L. (var. BH902). Further, the involvement of two key regulatory signaling molecules--auxin and nitric oxide (NO)--in Si-induced tolerance against Pi deficiency in barley was tested. Morphological attributes, photosynthetic parameters, oxidative stress markers (O2·-, H2O2, and MDA), antioxidant system (enzymatic--APX, CAT, SOD, GR, DHAR, MDHAR as well as non-enzymatic--AsA and GSH), NO content, and proline metabolism were the key traits that were assessed under different treatments. The P deficiency distinctly declined growth of barley seedlings, which was due to enhancement in oxidative stress leading to inhibition of photosynthesis. These results were also in parallel with an enhancement in antioxidant activity, particularly SOD and CAT, and endogenous proline level and its biosynthetic enzyme (P5CS). The addition of Si exhibited beneficial effects on barley plants grown in Pi-deficient medium as reflected in increased growth, photosynthetic activity, and redox balance through the regulation of antioxidant machinery particularly ascorbate-glutathione cycle. We noticed that auxin and NO were also found to be independently participating in Si-mediated improvement of growth and other parameters in barley roots under Pi deficiency. Data of gene expression analysis for PHOSPHATE TRANSPORTER1 (HvPHT1) indicate that Si helps in increasing Pi uptake as per the need of Pi-deficient barley seedlings, and also auxin and NO both appear to help Si in accomplishing this task probably by inducing lateral root formation. These results are suggestive of possible application of Si as a fertilizer to correct the negative effects of nutritional stresses in plants. Further research at genetic level to understand Si-induced mechanisms for mitigating Pi deficiency can be helpful in the development of new varieties with improved tolerance against Pi deficiency, especially for cultivation in areas with Pi-deficient soils.

Discriminatory performance of the pulpal inflammatory biomarkers; Interleukin-8 and TNF-α in patients with symptoms indicative of reversible and irreversible pulpitis: A diagnostic accuracy study.

AIM: The success of vital pulp treatment (VPT) procedures is dependent on an accurate diagnosis of the pulpal inflammatory condition. Compared with current subjective pulpal diagnostic tests, inflammatory molecular biomarkers involved in the pathogenesis of pulpitis represent potential objective indicators of the degree of pulpal inflammation. Therefore, the aim of this study was to quantify level of inflammatory biomarkers - Interleukin 8 (IL-8) and TNF-α in patients diagnosed with reversible pulpitis (RP), irreversible pulpitis (IR) and normal pulp (NP) and investigate their diagnostic accuracy in differentiating between healthy and inflamed conditions. METHODOLOGY: This prospective, cross-sectional study enrolled 72 patients aged 14-53 years with extremely deep carious lesions after establishing a clinical diagnosis of RP (n = 42), symptomatic IR (n = 22) and NP (n = 8). 50 µL of pulpal blood sample was collected from all the patients using a micropipette after pulpal exposure. The level of IL-8 and TNF-α was assessed in pg/mL using enzyme-linked immunosorbent assays. Mann-Whitney U test was applied to establish the association between IL-8/TNF-α level and degree of pulp inflammation. Receiver operating curve (ROC) analysis was carried out to calculate area under the curve (AUC) for RP versus IR. Cut-off values were established using Youden's index. RESULTS: IL-8 and TNF-α levels differed significantly between RP and IR groups (p ≤ .001). The median value of IL-8 in RP and IP groups was 259.8 pg/mL [187.5-310.0] and 1357.8 pg/mL [1036.7-2177.6] respectively. The AUC-ROC curve for RP versus IR was 0.997 with 95.5% sensitivity and 99.76% specificity. The median value of TNF-α in RP and IR groups was 75.4 pg/mL [62.7-95.8] and 157.6 pg/mL [94.1-347.3]. The AUC-ROC curve for TNF-α was 0.812 with a sensitivity and specificity of 59.1% and 92.1%, respectively. IL-8 and TNF-α levels were below detection levels for all NP samples. CONCLUSION: This study showed that pulpal blood could provide an excellent medium for establishing pulpal diagnosis under extremely deep carious lesions. The selected cytokines, IL-8 and TNF-α, demonstrated excellent discriminatory performance for reversible and irreversible pulpitis. Future studies should correlate the IL-8/TNF-α levels with VPT treatment outcomes.

Buprenorphine Affects the Initiation and Severity of Interleukin Induced Acute Pancreatitis in Mice.

Acute pancreatitis (AP) is a common disease with no targeted therapy and has varied outcomes ranging from spontaneous resolution to being lethal. While typically painful, AP can also be painless. Various agents, including opioids are used for pain control in AP; the risks, and benefits of which are often debated. Since experimental AP in mice is used to study the efficacy of potential therapies, we studied the effect of a commonly used opioid buprenorphine on the initiation and progression of AP. For this we administered extended-release buprenorphine subcutaneously prior to inducing the previously established severe AP model that uses Interleukins 12 and 18 (IL12,18) in genetically obese (ob/ob) mice and compared this to mice with AP but without the drug. Mice were monitored over 3 days and parameters of AP induction and progression were compared. Buprenorphine significantly reduced the serum amylase, lipase, pancreatic necrosis, and AP associated fat necrosis which is ubiquitous in obese mice and humans. Buprenorphine delayed the AP associated reduction of carotid artery pulse distention, and development of hypothermia, hastened renal injury, and muted the early increase in respiratory rate vs. IL12,18 alone. The site of buprenorphine injection appeared erythematous, inflamed, and microscopically showed thinning, loss of epidermal layers which had increased apoptosis. In summary, subcutaneous extended-release buprenorphine interfered with the induction of AP by reducing serum amylase, lipase, pancreatic and fat necrosis, the worsening of AP by delaying hypotension, hypothermia, while hastening renal injury, respiratory depression, and causing cutaneous injury at the site of injection.

Neutrophil-driven and interleukin-36γ-associated ocular surface inflammation in chronic Stevens-Johnson syndrome.

PURPOSE: This study aims to elucidate the tear proteome and understand the underlying molecular mechanisms involved in the ocular complications following Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN). METHODS: Mass spectrometry (MS) was performed to quantify the tear fluid proteins from chronic SJS/TEN patients (n = 22 eyes) and age- and gender-matched controls (n = 22 eyes). The candidate proteins were validated using ELISA (n = 80 eyes) in tear samples and immunohistochemistry (IHC; n = 12) in eyelid margin specimens. These proteins were compared for significant differences based on age, gender, disease duration, and ocular severity. RESULTS: A total of 1692 tear fluid proteins were identified, of which 470 were significantly differentially regulated in chronic SJS/TEN. The top 10 significantly upregulated proteins were neutrophil secretions including neutrophil elastase (p < .0001), defensin (p < .0001), and matrix metalloproteinase 8 (p < .0001). The presence of neutrophils was confirmed by the upregulation of IL-8 (p < .001) in tears, a key cytokine known for recruiting neutrophils. Additionally, positive expression of myeloperoxidase was observed in the keratinized eyelid margins of SJS/TEN to validate the presence of neutrophils. Among 41 unique proteins identified by MS, IL-36γ (p < .01) was expressed in three SJS/TEN patients and was confirmed in SJS/TEN tears and eyelid margins by ELISA and IHC, respectively. IL-36γ was specifically expressed in the superficial layers of eyelid margin keratinized conjunctiva. The majority of the significantly downregulated proteins were lacrimal gland secretions such as lacritin (p < .0001) and opiorphin (p < .002). Neutrophil elastase (p < .02) was significantly elevated in patients with severe eyelid margin keratinization. CONCLUSION: Our observations indicate a clear correlation between eyelid margin keratinization and the expression of IL-36γ, potentially mediated by neutrophils recruited via IL-8. Future experimental studies are needed to test the role of therapies targeting IL-8 and/or IL-36γ in reducing eyelid margin keratinization and its associated ocular complications in SJS/TEN.

Redox regulation by priming agents towards a sustainable agriculture.

Plant are sessile organisms that are often subjected to a multitude of environmental stresses, with the occurrence of these events being further intensified by global climate change. Crop species therefore require specific adaptations to tolerate climatic variability for sustainable food production. Plant stress results in excess accumulation of reactive oxygen species (ROS) leading to oxidative stress, and loss of cellular redox balance in the plant cells. Moreover, enhancement of cellular oxidation as well as oxidative signals have recently been recognized as crucial players in plant growth regulation under stress conditions. Multiple roles of redox regulation in crop production have been well documented, and major emphasis has focused on key redox-regulated proteins and non-protein molecules, such as NAD(P)H, thioredoxins, glutathione, glutaredoxins, peroxiredoxins, ascorbate, and reduced ferredoxin. These have been widely implicated in the regulation of (epi)genetic factors modulating growth and vigor of crop plants, particularly within an agricultural context. In this regard, priming with the employment of chemical and biological agents has emerged as a fascinating approach to improve plant tolerance against various abiotic and biotic stressors. Priming in plants is a physiological process, where prior exposure to specific stressors induces a state of heightened alertness, enabling a more rapid and effective defense response upon subsequent encounters with similar challenges. Priming is reported to play an important role in the regulation of cellular redox homeostasis, maximizing crop productivity under stress conditions and thus achieving yield security. By taking this into consideration, the present review is an up-to-date critical evaluation of promising plant priming technologies and their role in the regulation of redox components towards enhanced plant adaptations to extreme unfavorable environmental conditions. The challenges and opportunities of plant priming are addressed, with the aim to encourage future research in this field towards effective application in crop stress management including horticultural species.

The Labyrinthine Journey: Unveiling Obstacles in addressing Mental Health Challenges in Prisons and its Confluence with Medico-Legal and Pharmacological Perspectives.

This paper delves into the intricate realm of mental health issues within prisons including other correctional facilities, the intersectionality with legal and medical aspects, and the potential of pharmacology as a viable treatment modality. The prevalence and diverse array of mental disorders among incarcerated individuals are thoroughly examined, underscoring the imperative for all-encompassing interventions. The legal structure, hurdles encountered in delivering mental healthcare, and the indispensability of interdisciplinary cooperation are scrutinized. Furthermore, the effectiveness and moral implications of pharmaceutical interventions in correctional environments are deliberated upon. Conclusive suggestions are put forth to enhance mental healthcare provisions in prisons. The research paper endeavors to penetrate the labyrinthine complexities of mental health predicaments within correctional institutions, with a specific emphasis on the convergence of medico-legal facets and the plausible impact of pharmacological interventions. The study strives to elucidate the intricate nature of mental health challenges among incarcerated populations, considering the intricate interplay of socio-cultural, environmental, and psychological factors that contribute to their pervasiveness. By delving into these interconnected dimensions, the research aims to unlock prospective remedies capable of efficaciously meeting the mental health requisites of incarcerated individuals.

Accessing the behavior and awareness of veterinary professionals towards antimicrobials use and antimicrobial resistance in Indian district.

Introduction: Antimicrobial resistance (AMR) poses a significant public health threat, and understanding the awareness and practices of healthcare professionals is crucial for its mitigation. Since the animal sector plays a key role in India's economy, we decided to explore the understanding of Antimicrobial Use (AMU) and AMR among veterinary professionals. Methods: The study aimed to evaluate the awareness and behavior of veterinarians and para-veterinarians working in the Jhunjhunu district, Rajasthan, India, concerning AMU and AMR. Questionnaire surveys were administered to them with closed-ended questions. The data was collected and subjected to statistical analysis to derive meaningful insights. The key findings highlight notable differences in certain behavioral aspects of antibiotic prescription among the two groups. Results and Discussion: It appears that 53.8% of veterinarians as compared to 25.8% para-veterinarians do not surely inform farmers about the importance of adhering to antibiotic withdrawal periods, thereby failing to raise awareness about proper antibiotic use. Moreover, para-veterinarians (46.6%) tend to engage less in evidence-based antibiotic prescription than veterinarians (81%). Furthermore, both groups exhibit a lower frequency of advice on Antimicrobial Susceptibility Testing (ABST), essential for informed prescribing decisions. Most significantly, both groups show a tendency to prefer critically important antibiotics for prescription, raising concerns about the escalating threat of AMR. This study thus emphasizes the areas that need targeted interventions to enhance responsible antimicrobial usage and curb the growth of AMR in the region.

Nitric oxide acts upstream of indole-3-acetic acid in ameliorating arsenate stress in tomato seedlings.

After their discovery, nitric oxide (NO) and indole-3-acetic acid (IAA) have been reported as game-changing cellular messengers for reducing abiotic stresses in plants. But, information regarding their shared signaling in regulating metal stress is still unclear. Herein, we have investigated about the joint role of NO and IAA in mitigation of arsenate [As(V)] toxicity in tomato seedlings. Arsenate being a toxic metalloid increases the NPQ level and cell death while decreasing the biomass accumulation, photosynthetic pigments, chlorophyll a fluorescence, endogenous NO content in tomato seedlings. However, application of IAA or SNP to the As(V) stressed seedlings improved growth together with less accumulation of arsenic and thus, preventing cell death. Interestingly, addition of c-PTIO, {2-(4-carboxyphenyl)-4, 4, 5, 5-tetramethylimidazoline-1-oxyl-3-oxide, a scavenger of NO} and 2, 3, 5-triidobenzoic acid (TIBA, an inhibitor of polar auxin transport) further increased cell death and inhibited activity of GST, leading to As(V) toxicity. However, addition of IAA to SNP and TIBA treated seedlings reversed the effect of TIBA resulting into decreased As(V) toxicity. These findings demonstrate that IAA plays a crucial and advantageous function in NO-mediated reduction of As(V) toxicity in seedlings of tomato. Overall, this study concluded that IAA might be acting as a downstream signal for NO-mediated reduction of As(V) toxicity in tomato seedlings.

Knowledge and practices related to antibiotics among poultry producers and veterinarians in two Indian states.

Background: Antibiotics are frequently utilized in livestock, particularly poultry, for therapy and growth promotion, resulting in antimicrobial resistance. Multidrug-resistant bacteria are frequent in poultry samples from India. The purpose of this study was to better understand main antibiotic consumption patterns in poultry value chains, as well as antibiotic knowledge and practices among the stakeholders. Methods: A cross-sectional survey was conducted in Assam and Karnataka, India. The poultry farmers were interviewed on antibiotic usage, antibiotic knowledge, feeding practices, and preventive measures on the farm. Poultry farmers reported their veterinarians, and we also interviewed them on knowledge and practices related to antimicrobial use in poultry and antimicrobial resistance. Item response theory (IRT) was used to assess the association between the answers and demographic factors. Results: This survey interviewed 62 poultry farmers and 11 veterinarians. Small poultry farms with fewer than 4000 birds were owned by 51.6% of farmers. Most poultry farmers had heard about antibiotics, and 62.9% thought they cured all diseases. If one chicken is sick, 72.6% said others should be given antibiotics to prevent the disease. All veterinarians utilized tetracyclines, aminoglycosides, and cephalexin on the poultry farms. Over half (54.5%) stated antibiotics prevent diseases, and 72.7% said they treat and prevent diseases. Some (45.5%) said antibiotics boost growth. IRT analysis showed that 8 questions assessed a knowledge scale well. Univariable analysis showed that Assam farmers and women were likely to have have more knowledge. Conclusion: The poultry farmers were mostly unaware of the relation between antibiotic use and antimicrobial resistance. Despite being aware, the veterinarians agreed with use antibiotics as a prophylactic measure. It is vital that these stakeholders understand the repercussions of such widespread antibiotic use. In order to increase knowledge, frequent trainings and antimicrobial stewardship programmes with effective communication and incentives for behaviour change should be conducted.

Evolution of reactive oxygen species cellular targets for plant development.

Reactive oxygen species (ROS) are the key players in regulating developmental processes of plants. Plants have evolved a large array of gene families to facilitate the ROS-regulated developmental process in roots and leaves. However, the cellular targets of ROS during plant evolutionary development are still elusive. Here, we found early evolution and large expansions of protein families such as mitogen-activated protein kinases (MAPK) in the evolutionarily important plant lineages. We review the recent advances in interactions among ROS, phytohormones, gasotransmitters, and protein kinases. We propose that these signaling molecules act in concert to maintain cellular ROS homeostasis in developmental processes of root and leaf to ensure the fine-tuning of plant growth for better adaptation to the changing climate.

Effects of interaction of multiple large-scale atmospheric circulations on precipitation dynamics in China.

Different scenarios of precipitation, that lead to such phenomena as droughts and floods are influenced by concurrent multiple teleconnection factors. However, the multivariate relationship between precipitation indices and teleconnection factors, including large-scale atmospheric circulations and sea surface temperature signals in China, is rarely explored. Understanding this relationship is crucial for drought early warning systems and effective response strategies. In this study, we comprehensively investigated the combined effects of multiple large-scale atmospheric circulation patterns on precipitation changes in China. Specifically, Pearson correlation analysis and Partial Wavelet Coherence (PWC) were used to identify the primary teleconnection factors influencing precipitation dynamics. Furthermore, we used the cross-wavelet method to elucidate the temporal lag and periodic relationships between multiple teleconnection factors and their interactions. Finally, the multiple wavelet coherence analysis method was used to identify the dominant two-factor and three-factor combinations shaping precipitation dynamics. This analysis facilitated the quantification and determination of interaction types and influencing pathways of teleconnection factors on precipitation dynamics, respectively. The results showed that: (1) the Atlantic Multidecadal Oscillation (AMO), EI Niño-Southern Oscillation (ENSO), East Asia Summer Monsoon (EASM), and Indian Ocean Dipole (IOD) were dominant teleconnection factors influencing Standardized Precipitation Index (SPI) dynamics; (2) significant correlation and leading or lagging relationships at different timescales generally existed for various teleconnection factors, where AMO was mainly leading the other factors with positive correlation, while ENSO and Southern Oscillation (SO) were mainly lagging behind other factors with prolonged correlations; and (3) the interactions between teleconnection factors were quantified into three types: enhancing, independent and offsetting effects. Specifically, the enhancing effect of two-factor combinations was stronger than the offsetting effect, where AMO + NAO (North Atlantic Oscillation) and AMO + AO (Atlantic Oscillation) had a larger distribution area in southern China. Conversely, the offsetting effect of three-factor combinations was more significant than that of the two-factor combinations, which was mainly distributed in northeast and northwest regions of China. This study sheds new light on the mechanisms of modulation and pathways of influencing various large-scale factors on seasonal precipitation dynamics.

The Bacterial Quorum-Sensing Signal 2-Aminoacetophenone Rewires Immune Cell Bioenergetics through the PGC-1α/ERRα Axis to Mediate Tolerance to Infection.

How bacterial pathogens exploit host metabolism to promote immune tolerance and persist in infected hosts remains elusive. To achieve this, we show that Pseudomonas aeruginosa (PA), a recalcitrant pathogen, utilizes the quorum sensing (QS) signal 2-aminoacetophenone (2-AA). Here, we unveil how 2-AA-driven immune tolerization causes distinct metabolic perturbations in macrophages' mitochondrial respiration and bioenergetics. We present evidence indicating that these effects stem from a decrease in pyruvate transport into mitochondria. This reduction is attributed to decreased expression of the mitochondrial pyruvate carrier (MPC1), which is mediated by diminished expression and nuclear presence of its transcriptional regulator, estrogen-related nuclear receptor alpha (ERRα). Consequently, ERRα exhibits weakened binding to the MPC1 promoter. This outcome arises from the impaired interaction between ERRα and the peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). Ultimately, this cascade results in diminished pyruvate influx into mitochondria and consequently reduced ATP production in tolerized macrophages. Exogenously added ATP in infected macrophages restores the transcript levels of MPC1 and ERR-α and enhances cytokine production and intracellular bacterial clearance. Consistent with the in vitro findings, murine infection studies corroborate the 2-AA-mediated long-lasting decrease in ATP and acetyl-CoA and its association with PA persistence, further supporting this QS signaling molecule as the culprit of the host bioenergetic alterations and PA persistence. These findings unveil 2-AA as a modulator of cellular immunometabolism and reveal an unprecedent mechanism of host tolerance to infection involving the PGC-1α/ERRα axis in its influence on MPC1/OXPHOS-dependent energy production and PA clearance. These paradigmatic findings paving the way for developing treatments to bolster resilience to pathogen-induced damage. Given that QS is a common characteristic of prokaryotes, it is likely that 2-AA-like molecules with similar functions may be present in other pathogens.

Histopathological studies of nonhuman primates exposed to supralethal doses of total- or partial-body radiation: influence of a medical countermeasure, gamma-tocotrienol.

Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses.

Scale-up of microbial lipid and bioethanol production from oilcane.

Microbial oils are a sustainable biomass-derived substitute for liquid fuels and vegetable oils. Oilcane, an engineered sugarcane with superior feedstock characteristics for biodiesel production, is a promising candidate for bioconversion. This study describes the processing of oilcane stems into juice and hydrothermally pretreated lignocellulosic hydrolysate and their valorization to ethanol and microbial oil using Saccharomyces cerevisiae and engineered Rhodosporidium toruloides strains, respectively. A bioethanol titer of 106 g/L was obtained from S. cerevisiae grown on oilcane juice in a 3 L fermenter, and a lipid titer of 8.8 g/L was obtained from R. toruloides grown on oilcane hydrolysate in a 75 L fermenter. Oil was extracted from the R. toruloides cells using supercritical CO2, and the observed fatty acid profile was consistent with previous studies on this strain. These results demonstrate the feasibility of pilot-scale lipid production from oilcane hydrolysate as part of an integrated bioconversion strategy.