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Bacteria can quickly adapt to sub-lethal concentrations of antibiotics. Several stress and DNA repair genes contribute to this adaptation process. However, the pathways leading to adaptation by acquisition of de novo mutations remain poorly understood. This study explored the roles of DNA polymerase IV (dinB) and catalase HP2 (katE) in E. coli's adaptation to amoxicillin. These genes are thought to play essential roles in beta-lactam resistance-dinB in increasing mutation rates and katE in managing oxidative stress. By comparing the adaptation rates, transcriptomic profiles, and genetic changes of wild-type and knockout strains, we aimed to clarify the contributions of these genes to beta-lactam resistance. While all strains exhibited similar adaptation rates and mutations in the frdD gene and ampC operon, several unique mutations were acquired in the ΔkatE and ΔdinB strains. Overall, this study distinguishes the contributions of general stress-related genes on the one hand, and dinB, and katE on the other hand, in development of beta-lactam resistance., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2025 Teichmann et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

While stress increases vulnerability to development of addiction, the recruitment of corticotropin releasing factor (CRF) with excessive drug use heightens the risk of stress-induced relapse. CRF signaling is transmitted via CRF1 and CRF2 receptors, but the roles of these receptors in heroin self-administration and related neuroadaptations of the CRF system within mesolimbic brain loci are not well understood. In this study, we first investigated the causal role of CRF1 and CRF2 receptors in heroin self-administration. Intracerebroventricular (ICV) microinjections of antalarmin (a CRF1 antagonist) or astressin-2B (a CRF2 antagonist) caused brief, dose-dependent reductions in heroin self-administration in female rats, suggesting that these receptors play a critical role in heroin-motivated behaviors. We then used western blotting to examine neuroadaptive changes to CRF1 and CRF2 receptor expression in key forebrain and midbrain regions associated with opioid addiction. Female Long Evans rats treated with escalating doses of heroin for 16 days demonstrated significantly higher naloxone-precipitated withdrawal symptoms than saline-treated rats. Heroin-treated rats showed a significant decrease in CRF1 receptor protein expression in the ventral tegmental area (VTA) and an increase in the nucleus accumbens (NAc) but no changes in the prefrontal cortex (PFC), insula, dorsal striatum (dSTR), dorsal hippocampus (dHippo), anterior hypothalamus (HYPTH), amygdala, or substantia nigra (SN) as compared to saline-treated rats. After chronic heroin exposure, CRF2 receptor expression was significantly downregulated in the dHippo, VTA and HYPTH but not in the other brain regions we investigated. The results of this study suggest that: (1) CRF1 and CRF2 receptors play an important role in self-administration and (2) heroin exposure may lead to region-specific neuroadaptation of CRF1 and CRF2 receptors. Such neuroadaptations might in part contribute to the continuation of drug use and stress-induced relapse., Competing Interests: Conflict of interest statement The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as potential conflict of interest., (Copyright © 2025 Elsevier Inc. All rights reserved.)

We examined the effect of habitual preexercise caffeine supplementation on training-induced adaptations to exercising systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), and double product (DP). Young women (means ± SD; 24 ± 7 yr) were randomized to a caffeine (120 mg) supplement (CAF; n = 17) or placebo (PLA; n = 16) group, completed 6 wk of high-intensity exercise training on three nonconsecutive days per week, and supplemented with CAF or PLA 30-60 min before exercise or else upon waking. Before (PRE) and after (POST) the intervention, SBP, DBP, and HR were measured and PP and DP were calculated, at rest and during fixed-power exercise at 50 and 75 W. Statistical analyses included three-way mixed-factorial ANOVAs with post hoc comparisons as necessary. Group × intensity × time interactions were observed for SBP ( P = 0.0105) and DP ( P = 0.003). SBP and DP increased with increasing exercise intensity at PRE and POST in both groups. However, although SBP and DP decreased PRE to POST at 50 and 75 W in PLA, SBP and DP did not change at any intensity from PRE to POST in CAF. An intensity × time interaction was observed for DBP ( P = 0.006) indicating no change in resting DBP, but reductions from PRE to POST at 50 and 75 W that were independent of group. Main effects of intensity ( P < 0.0001) and time ( P = 0.03) were observed for HR, and a main effect of intensity was observed for PP ( P < 0.0001). Habitual caffeine supplementation blunted training-induced reductions in exercising SBP and DP. Individuals may wish to avoid preexercise supplementation if seeking to maximize the BP-lowering benefits of exercise. NEW & NOTEWORTHY Habitual preexercise caffeine consumption prevented reductions in exercising systolic blood pressure and double product induced by 6 wk of high-intensity exercise in women. Therefore, our findings indicate that habitual preexercise caffeine supplementation may impede beneficial hemodynamic adaptations of exercise training in healthy, young women.

Mitochondria are metabolic hubs that govern skeletal muscle health. Although exercise has been established as a powerful inducer of quality control processes that ultimately enhance mitochondrial function, there are currently limited pharmaceutical interventions available that emulate exercise-induced mitochondrial adaptations. To investigate a novel candidate for this role, we examined sulforaphane (SFN), a naturally occurring compound found in cruciferous vegetables. SFN has been documented as a potent antioxidant inducer through its activation of the nuclear factor erythroid 2-related factor 2 (Nrf-2) antioxidant response pathway. However, its effects on muscle health have been underexplored. To investigate the interplay between chronic exercise and SFN, C2C12 myotubes were electrically stimulated to model chronic contractile activity (CCA) in the presence or absence of SFN. SFN promoted Nrf-2 nuclear translocation, enhanced mitochondrial respiration, and upregulated key antioxidant proteins including catalase and glutathione reductase. These adaptations were accompanied by reductions in cellular and mitochondrial reactive oxygen species (ROS) emission. Signaling toward biogenesis was enhanced, demonstrated by increases in mitochondrial transcription factor A (TFAM), peroxisome proliferator-activated receptor-gamma coactivator (PGC)-1α nuclear translocation, PGC-1α promoter activity, mitochondrial content, and organelle branching, suggestive of a larger, more interconnected mitochondrial pool. These mitochondrial adaptations were accompanied by an increase in lysosomal proteins, suggesting coordinated regulation. There was no difference in mitochondrial and antioxidant-related proteins between CCA and non-CCA SFN-treated cells. Our data suggest that SFN activates signaling cascades that are common to those produced by contractile activity, indicating that SFN-centered therapeutic strategies may improve the mitochondrial phenotype in skeletal muscle. NEW & NOTEWORTHY Nrf-2 is a transcription factor that has been implicated in mitigating oxidative stress and regulating mitochondrial homeostasis. However, limited research has demonstrated how Nrf-2-mediated adaptations compare with those produced by exercise. To investigate this, we treated myotubes with Sulforaphane, a well-established Nrf-2 activator, and combined this with stimulation-induced chronic contractile activity to model exercise training. Our work is the first to establish that sulforaphane mimics training-induced mitochondrial adaptations, including enhancements in respiration, biogenesis, and dynamics.

Necrotizing enterocolitis (NEC) is a severe intestinal disease of multifactorial origin that primarily affects premature infants. Approximately 27% of NEC babies develop short gut (SG) secondary to extensive intestinal resection, and 10% will have chronic dependence on total parenteral nutrition. We evaluated the Botox treatment in SG model rats. Twenty-day-old weanling male rats (weight range 38-70 g, n=72) were divided into four groups (n=18 each): 1) Control (fed a regular liquid diet); 2) Botox (Control submitted to laparotomy and intestinal injection of Botox®); 3) SG (short gut); and 4) SG and Botox (SG+Botox®). After seven post-operative days, samples were collected for biometrics [body weight (BW), intestine weight (IW) and IW/BW ratio (IBR), and intestine length (IL) and height (IH)], histometric analysis [villous height (VH), crypt depth (CD), muscular thickness (MT), and PCNA index)], and intestinal transit time (ITT). BW, IW, and IL decreased in SG (P<0.05). IH, VH, and PCNA index increased in Botox groups [Control = SG < Botox and SG+Botox (P<0.05)], CD increased in Botox, SG, and SG+Botox (P<0.005), and MT was higher in SG and SG+Botox. Botox groups had lower ITT (P<0.05). Botox provided dilatation and histological changes in SG. These findings suggested that Botox improved adaptation and might be applied in SG with promising results.

Antibiotic tolerance presents a significant challenge in eradicating bacterial infections, as tolerant strains can survive antibiotic treatment, contributing to the recurrence of infections and the development of resistance. However, unlike antibiotic resistance, tolerance is not detectable by standard susceptibility assays such as minimal inhibitory concentration (MIC) tests. Consequently, antibiotic tolerance often goes unnoticed in clinical settings. Bacterial metabolism is closely linked to antibiotic efficacy, and thus presents as a potential target for novel diagnostic methods. Recent advancements in nuclear magnetic resonance (NMR) spectroscopy, including dynamic nuclear polarization (DNP-NMR), enable a non-invasive real-time approach to analyzing bacterial metabolism. In this study, we applied both 1 H and in-cell 13 C NMR spectroscopy to investigate metabolic adaptations in a tolerance-evolved Salmonella Typhimurium strain, C10, developed through ten cycles of ampicillin treatment. Our results demonstrated that despite similar MICs and growth rates, the C10 strain exhibited a 25-fold increase in tolerance compared to the wild-type, while exhibiting lower metabolic activity. Under ampicillin stress, however, the C10 strain maintained higher metabolic activity and demonstrated greater resilience in glucose consumption and metabolite production relative to the wild-type. Using DNP-NMR, rapid metabolic shifts in the C10 strain were identified within 10 minutes of exposure to high concentrations of ampicillin, characterized by accumulation of key metabolites such as pyruvate and acetate. Overall, our findings underscore the potential of real-time NMR-based analyses to provide deeper insights into antibiotic tolerance and distinguish between susceptible and tolerant bacterial strains.

Copper(II) oxide nanoparticles (CuO NPs) are used in different industries and agriculture, thus leading to their release to the environment, which raises concerns about their ecotoxicity and biosafety. The main toxicity mechanism of nanometals is oxidative stress as a result of the formation of reactive oxygen species caused by metal ions released from nanoparticles. Bacterial biofilms are more resistant to physical and chemical factors than are planktonic cells due to the extracellular polymeric matrix (EPM), which performs a protective function. Hydrocarbon-oxidizing bacteria of the genus Rhodococcus , well-known biodegraders of toxic organic pollutants and bioremediation agents, are capable of producing biofilms, which, as we proposed, are more resistant to metal nanoparticles, while the particular adaptation mechanisms have not yet been clarified. In this study, we study the adaptation mechanisms of Rhodococcus rhodochrous IEGM 1363 biofilms to CuO NPs in a wide range of concentrations (0.001-0.1 g/L), including morphological and ultrastructural cell alterations. The results obtained on the long-term dynamics (≤72 h) and localization of EPM structural components, in particular, lipids, polysaccharides, and proteins, indicated their important role in the complex adaptive response of alkanotrophic Rhodococcus to oxidative stress caused by copper nanooxide. The observed changes in the ultrastructure and element composition included binding of CuO nanoparticles by the cell wall to prevent their penetration inside cells and intracellular accumulation of potassium, magnesium, phosphorus, and sulfur in electron-dense inclusions, which may be associated with a metabolic stress reaction. Understanding the mechanisms of interaction between nanometals and Rhodococcus biofilms will contribute to the development of biocatalysts based on immobilized bacterial cells and bioremediation methods.

The current investigation assessed the beneficial impacts of dietary sodium chloride (NaCl) on the growth performance, oxidant/antioxidant, and immune responses of Nile tilapia (Oreochromis niloticus) and its adaptability to different salinity levels. After acclimating the fish to the laboratory conditions for 2 weeks, the acclimated fish (10.5 ± 0.16 g) were randomly distributed into 25 110-L rectangular glass tanks (15 fish/tank) to represent five groups in five replicates. The fish were fed with experimental feeds fortified with 0.0 (control), 5, 10, 15, and 20 g NaCl/kg feed for 60 days. Following the nutritional experiment, fish of all groups were adapted to different salinity levels from 0 to 32 g /L for a further 3 weeks, during which fish mortality was recorded. Blood samples were taken after the feeding trial and at a salinity level of 24 g/L. Growth performance and hematological parameters (WBCs, RBCs, hemoglobin, and hematocrit), total protein, albumin, globulin, digestive enzymes, antioxidant activity, and immunity status were markedly improved with increased NaCl rates in the fish diets up to 10 g/kg feed, after which all previous parameters were declined. On the other hand, feeding fish on a diet containing 10 g NaCl/kg feed showed substantially lower levels of cortisol, glucose, cholesterol, triglycerides, aspartate transaminase (AST), alanine transaminase (ALT), and malondialdehyde (MDA). Exposing the control fish group to salinity stress (32 g/L) for 3 weeks markedly decreased their digestive enzyme activity, immunity status, and antioxidant response, along with significant increases in cortisol, glucose, cholesterol, triglycerides, AST, ALT, and MDA levels. Conversely, feeding fish on a diet containing 10 g NaCl/kg feed alleviated the negative impacts of salinity stress and helped fish to tolerate salinity stress up to 24 g/L., Competing Interests: Declarations. Ethical approval: The authors followed all applicable guidelines (international, national, and/or institutional) for caring for and using fish under experimental conditions while designing the experiments. The animal studies adhered to the norms and criteria set out by ARRIVE ( https://arriveguidelines.org/ ). The Agricultural Research Center, Giza, Egypt, authorized all operations in accordance with the IACUC protocol No.: ARC-CLAR-68–23. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2025. The Author(s).)

Ethanol tolerant Saccharomyces cerevisiae is compulsory for ethanol production in starch based biorefinery, especially during high-gravity fermentation. In this study, adaptive evolution with increased initial ethanol concentrations as a driving force was harnessed for achieving ethanol tolerant S. cerevisiae. After evolution, an outstanding ethanol tolerant strain was screened, which contributed to significant improvements in glucose consumption and ethanol production in scenarios of 300 g/L initial glucose, high solid loadings (30 wt%, 33 wt%, 35 wt% and 40 wt%) of corn, and high solid loadings (30 wt% and 33 wt%) of cassava, compared with the original strain. Genome re-sequencing was applied for the evolved strain, and 504 sense mutations in 205 genes were detected, among which PAM1 gene was demonstrated related to the elevated ethanol tolerance. In sum, this study provided a practical approach for obtaining ethanol tolerant strain and the identified PAM1 gene enhanced our understanding on ethanol tolerant mechanism, as well as provided a target basis for rational metabolic engineering., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier B.V.)

Industrial pollution is a major driver of ecosystem degradation, but it can also act as a driver of contemporary evolution. As a result of intense mining activity during the Industrial Revolution, several rivers across the southwest of England are polluted with high concentrations of metals. Despite the documented negative impacts of ongoing metal pollution, brown trout (Salmo trutta L.) survive and thrive in many of these metal-impacted rivers. We used population genomics, transcriptomics, and metal burdens to investigate the genomic and transcriptomic signatures of potential metal tolerance. RADseq analysis of six populations (originating from three metal-impacted and three control rivers) revealed strong genetic substructuring between impacted and control populations. We identified selection signatures at 122 loci, including genes related to metal homeostasis and oxidative stress. Trout sampled from metal-impacted rivers exhibited significantly higher tissue concentrations of cadmium, copper, nickel and zinc, which remained elevated after 11 days in metal-free water. After depuration, we used RNAseq to quantify gene expression differences between metal-impacted and control trout, identifying 2042 differentially expressed genes (DEGs) in the gill, and 311 DEGs in the liver. Transcriptomic signatures in the gill were enriched for genes involved in ion transport processes, metal homeostasis, oxidative stress, hypoxia, and response to xenobiotics. Our findings reveal shared genomic and transcriptomic pathways involved in detoxification, oxidative stress responses and ion regulation. Overall, our results demonstrate the diverse effects of metal pollution in shaping both neutral and adaptive genetic variation, whilst also highlighting the potential role of constitutive gene expression in promoting metal tolerance., (© 2024 The Author(s). Molecular Ecology published by John Wiley & Sons Ltd.)

Pretreatment of Physcomitrium patens with abscisic acid (ABA) has been shown to induce desiccation tolerance. While previous research suggests that ABA-induced production of proteins and soluble sugars contributes to desiccation stress tolerance, additional mechanisms underlying this tolerance remain unclear. In this study, we found that ABA pretreatment led to increased levels of digalactosyl diacylglycerol (DGDG), phosphatidylcholine (PC), and phosphatidylinositol (PI), along with a decrease in monogalactosyl diacylglycerol (MGDG). These changes elevated the MGDG/DGDG and PC/phosphatidylethanolamine (PE) ratios, potentially stabilizing membranes and enhancing desiccation tolerance. Furthermore, ABA pretreatment effectively prevented membrane lipid degradation during desiccation and subsequent rehydration. These findings highlight ABA's role in desiccation tolerance through membrane lipid modulation, providing new insights into stress tolerance mechanisms in bryophytes., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Opioid overdose is the leading cause of accidental death in the United States and remains a major public health concern, despite significant resources aimed at combating opioid misuse. Neurobiological research to elucidate molecular and cellular consequences of opioid exposure is required to define avenues to explore for reversal of opioid-induced neuroadaptations. Opioids impart well-documented regulation of the transcriptome and epigenetic modifications in the brain, but opioid-induced epitranscriptomic posttranscriptional regulation of RNA is vastly understudied. N6-methyladenosine (m6A) RNA methylation is significantly enriched in the brain and involved in learning, memory, and reward. m6A modifications have not been studied in opioid use disorder, despite being the most common RNA modification. We detected significant regulation of m6A-modifying enzymes in rat primary cortical cultures following morphine treatment, including AlkB Homolog 5 (Alkbh5). The m6a demethylase ALKBH5 functions as an m6A eraser, removing m6A modifications from mRNA. We hypothesized that chronic opioid treatment regulates m6A modifications through modulation of Alkbh5 and profiled m6A modifications in primary cortical cultures following chronic morphine treatment and Alkbh5 knock-down. We observed differential regulation of m6A modifications for a common set of transcripts following morphine or Alkbh5 knock-down, and the two treatments elicited concordant m6A epitranscriptomic profiles, suggesting that a subset of morphine-driven m6A modifications may be mediated through downregulation of Alkbh5 in cortical cultures. Gene Ontology terms of commonly regulated transcripts included serotonin secretion, synapse disassembly, neuron remodeling, and immune response. Thus, we conclude that morphine can drive epitranscriptomic changes, a subset of which may occur in an Alkbh5-dependent manner., Competing Interests: Declarations. Ethics Approval: The animal study protocol was approved by Temple University’s Institutional Animal Care and Use Committee (protocol # 4888; April 2022). Consent to Participate: Not applicable. Consent for Publication: All authors have read and agreed to the published version of the manuscript. Competing Interests: The authors declare no competing interests., (© 2024. The Author(s).)

The growing phase of laying hens is crucial for growth and development due to its direct impact on their productivity during laying phase. During initial growth phase, intestinal tract undergoes rapid development which requires plenty of nutrients to help laying hens grow and mature. This study investigated the effect of Alanyl-Glutamine (Aln-Gln) levels on growth performance, ileal morphology and transcriptomic analysis of growing Hy-line brown hens. A total of 480 day old Hy-line brown chicks having similar body weight (BW) were randomly divided to be fed diets having 0%, 0.1%, 0.2% and 0.3% Aln-Gln for 6-wks (8 replicates/group, 15 birds/replicate). One bird from every pen was slaughtered and morphological parameters of ileum were evaluated. Results taken on day 42 revealed an improved average daily gain (ADG), final body weight (FBW) and feed-to-gain ratio (F/G) in the birds that consumed 0.2% and 0.3% Aln-Gln supplemented diet (P < 0.05). Ileal morphological assays showed that villus height, villus width and villus to crypts ratio (V/C) were significantly increased at 42 days of age in birds fed diets with 0.2% Aln-Gln (P<0.05). The RNA sequencing (RNA-Seq) was executed to identify differentially expressed genes (DEGs) among groups that found 2265 DEGs (1256 up-regulated; 1009 down-regulated) in ileum tissue. According to the Kyoto Encyclopedia of Genes (KEGG) and Genomic Pathway Enrichment Analysis, majority of DEGs indicated change in metabolic pathways. Genes related to growth factors, intestinal morphology and protein metabolism were up-regulated in test groups as compared to control group. In conclusion, addition of Aln-Gln to the diet improved growth performance and ileum development in growing hens; transcriptomic analysis revealed up-regulation of genes related to growth and intestinal morphology., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Haiming Yang reports financial support was provided by Huai'an science and technology planning project. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Arsenic poses a global threat to living organisms, compromising crop security and yield. Limited understanding of the transcriptional network integrating arsenic-tolerance mechanisms with plant developmental responses hinders the development of strategies against this toxic metalloid. Here, we conducted a high-throughput yeast one-hybrid assay using as baits the promoter region from the arsenic-inducible genes ARQ1 and ASK18 from Arabidopsis thaliana, coupled with a transcriptomic analysis, to uncover novel transcriptional regulators of the arsenic response. We identified the GLABRA2 (GL2) transcription factor as a novel regulator of arsenic tolerance, revealing a wider regulatory role beyond its established function as a repressor of root hair formation. Furthermore, we found that ANTHOCYANINLESS2 (ANL2), a GL2 subfamily member, acts redundantly with this transcription factor in the regulation of arsenic signaling. Both transcription factors act as repressors of arsenic response. gl2 and anl2 mutants exhibit enhanced tolerance and reduced arsenic accumulation. Transcriptional analysis in the gl2 mutant unveils potential regulators of arsenic tolerance. These findings highlight GL2 and ANL2 as novel integrators of the arsenic response with developmental outcomes, offering insights for developing safer crops with reduced arsenic content and increased tolerance to this hazardous metalloid., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Chronic ethanol exposure produces neuroadaptations in the medial prefrontal cortex (mPFC) that are thought to facilitate maladaptive behaviors that interfere with recovery from alcohol use disorder. Despite evidence that different cortico-subcortical projections play distinct roles in behavior, few studies have examined the physiological effects of chronic ethanol at the circuit level. The rostromedial tegmental nucleus (RMTg) is functionally altered by chronic ethanol exposure. Our recent work identified dense input from the mPFC to the RMTg, yet the effects of chronic ethanol exposure on this circuitry is unknown. In the current study, we examined physiological changes after chronic ethanol exposure in prelimbic (PL) and infralimbic (IL) mPFC neurons projecting to the RMTg. Adult male Long-Evans rats were injected with fluorescent retrobeads into the RMTg and rendered dependent using a 14-day chronic intermittent ethanol (CIE) vapor exposure paradigm. Whole-cell patch-clamp electrophysiological recordings were performed in fluorescently-labeled (RMTg-projecting) and -unlabeled (projection-undefined) layer 5 pyramidal neurons 7-10 days following ethanol exposure. CIE exposure significantly increased intrinsic excitability as well as spontaneous excitatory and inhibitory postsynaptic currents (sE/IPSCs) in RMTg-projecting IL neurons. In contrast, no lasting changes in excitability were observed in RMTg-projecting PL neurons, although a CIE-induced reduction in excitability was observed in projection-undefined PL neurons. CIE exposure also increased the frequency of sEPSCs in RMTg-projecting PL neurons. These data uncover novel subregion- and circuit-specific neuroadaptations in the mPFC following chronic ethanol exposure and reveal that the IL mPFC-RMTg projection is uniquely vulnerable to long-lasting effects of chronic ethanol exposure. This article is part of the Special Issue on "PFC circuit function in psychiatric disease and relevant models"., Competing Interests: Declaration of Competing interest All authors declare no conflicts of interest., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

High inhibitor concentrations in lignocellulose feedstock negatively affect the degradation rate of biodetoxification strains. This study designed two adaptive laboratory evolutions in solid substrate and liquid medium to boost the biodetoxification capacity of P. variotii to high titers of lignocellulose-derived inhibitors, resulting in two evolved strains AC70 and ZW70. The results showed that the evolutionary adaptation in liquid medium could better boost the acetic acid assimilation compared to that on solid substrate. Transcriptional analysis revealed that the evolved strains exhibited a significant upregulation of adh, acs, ach1, and ackA directly related to the initial steps of acetate and furan aldehydes metabolisms. ZW70 strain can effectively remove the high concentration inhibitors cocktail from the hydrolysates derived from pretreated wheat straw and furfural residues. The biodetoxified hydrolysates by ZW70 were successfully used for cellulose chiral L-lactic acid production with the titers of ∼110 g/L, which were over 20 % higher than that detoxified by parental strain., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Soil nitrogen (N) significantly influences the interaction between plants and pathogens, yet its impact on host defenses and pathogen strategies via alterations in plant metabolism remains unclear. Through metabolic and genetic studies, this research demonstrates that high-N-input exacerbates tomato bacterial wilt by altering γ-aminobutyric acid (GABA) metabolism of host plants. Under high-N conditions, the nitrate sensor NIN-like protein 7 (SlNLP7) promotes the glutamate decarboxylase 2/4 (SlGAD2/4) transcription and GABA synthesis by directly binding to the promoters of SlGAD2/4. The tomato plants with enhanced GABA levels showed stronger immune responses but remained susceptible to Ralstonia solanacearum. This led to the discovery that GABA produced by the host actually heightens the pathogen's virulence. We identified the R. solanacearum LysR-type transcriptional regulator OxyR protein, which senses host-derived GABA and, upon interaction, triggers a response involving protein dimerization that enhances the pathogen's oxidative stress tolerance by activating the expression of catalase (katE/katGa). These findings reveal GABA's dual role in activating host immunity and enhancing pathogen tolerance to oxidative stress, highlighting the complex relationship between tomato plants and R. solanacearum, influenced by soil N status., (© 2024 The Author(s). New Phytologist © 2024 New Phytologist Foundation.)

Strigolactones (SLs) play crucial roles in both plant growth and stress responses. However, their impact on the secondary metabolites of woody plants remains elusive. Here, we found that exogenous strigolactone analogue GR24 positively regulates tea plant flavor secondary metabolites, concurrently inhibiting caffeine biosynthesis and promoting the accumulation of caffeine catabolic pathway products. In this process, SL directly or indirectly inhibits the expression of CsSAMSs by inducing CsbHLH80, thereby reducing caffeine biosynthesis. Furthermore, CsbHLH80 enhances caffeine degradation, leading to increased allantoin. Under normal conditions, heightened allantoin reduces abscisic acid (ABA) accumulation. This inhibition reverses under drought stress. Increased ABA significantly enhances tea plant tolerance to both drought and Phyllosticta theicola Petch. In summary, this study offers novel insights for improving tea plant adaptation and quality in arid regions, particularly emphasizing the selection of stress-tolerant varieties and the refinement of production measures with a focus on high-quality production and environmentally friendly biological control methods., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

The mesolimbic reward system originating from dopamine neurons in the ventral tegmental area (VTA) of the midbrain shows a profound reduction in function during cannabinoid withdrawal. This condition may underlie aversive states that lead to compulsive drug seeking and relapse. The lateral habenula (LHb) exerts negative control over the VTA via the GABA rostromedial tegmental nucleus (RMTg), representing a potential convergence point for drug-induced opponent processes. We hypothesized that the LHb-RMTg pathway might be causally involved in the hypodopaminergic state during cannabinoid withdrawal. To induce Δ 9 -tetrahydrocannabinol (THC) dependence, adult male Sprague-Dawley rats were treated with THC (15 mg/kg, i.p.) twice daily for 6.5-7 days. Administration of the cannabinoid antagonist rimonabant (5 mg/kg, i.p.) precipitated a robust behavioral withdrawal syndrome, while abrupt THC suspension caused milder signs of abstinence. Extracellular single unit recordings confirmed a marked decrease in the discharge frequency and burst firing of VTA dopamine neurons during THC withdrawal. The duration of RMTg-evoked inhibition was longer in THC withdrawn rats. Additionally, the spontaneous activity of RMTg neurons and of LHb neurons was strongly depressed during cannabinoid withdrawal. These findings support the hypothesis that functional changes in the habenulo-mesencephalic circuit are implicated in the mechanisms underlying substance use disorders.

Little information is known about the long-term effects of nanoplastics (NPs) in aquatic environments, especially under environmental-related scenarios. Herein, three differently charged NPs (nPS, nPS-NH 2 , and nPS-COOH) were exposed at an environmentally realistic concentration (10 μg/L) for 100 days to explore the variation of primary productivity (i.e., algae) in aquatic ecosystems. Our results demonstrated that the algae adapted to all three types of NPs by enhancing the algal number (by 10.34-16.52%), chlorophyll a (by 11.28-17.65%), and carbon-fixing enzyme activity (by 49.19-68.33%), which were further confirmed by the exposure results from natural water culturing experiments. Based on the algal chloroplast number and biovolume at the individual level, only nPS caused algal differentiation into two heterogeneous subpopulations (54.92 vs 45.08%), while nPS-NH 2 and nPS-COOH did not cause the differentiation of the algal population. Moreover, the molecular adaptation mechanisms of algae to NPs were unraveled by integrating epigenomics and transcriptomics. Mean methylation rates of algae on exposure to nPS, nPS-NH 2 , and nPS-COOH were significantly elevated. In addition, the direction of gene expression regulation via differentially methylated regions associated with genes when exposed to nPS-COOH was distinct from those of nPS and nPS-NH 2 . Our results highlight the importance of assessing the long-term ecotoxicity of NPs and provide useful information for understanding the effect of NPs on aquatic ecosystems.

Recent studies have shown that pharmacologic weight loss with glucagon-like peptide-1 receptor agonists (GLP-1 RAs) and combination therapies is approaching magnitudes achieved with surgery. However, as more weight loss is achieved, there is concern for potential adverse effects on muscle quantity, composition, and function. This primer aims to address whether muscle-related changes associated with weight loss treatments such as GLP-1 RAs may be maladaptive (ie, adversely affecting muscle health or function), adaptive (ie, a physiologic response to weight loss maintaining or minimally affecting muscle health or function), or perhaps an enhanced response to weight loss (ie, improved muscle health or function after treatment). Based on contemporary evidence with the addition of studies using magnetic resonance imaging, skeletal muscle changes with GLP-1 RA treatments appear to be adaptive: changes in muscle volume z-score indicate a change in muscle volume that is commensurate with what is expected given aging, disease status, and weight loss achieved, and the improvement in insulin sensitivity and muscle fat infiltration likely contributes to an adaptive process with improved muscle quality, lowering the probability for loss in strength and function. Nevertheless, factors such as older age and prefrailty may influence the selection of appropriate candidates for these therapies because of risk for sarcopenia. Several pharmacologic treatments to maintain or improve muscle mass designed in combination with GLP-1-based therapies are under development. For future development of GLP-1-based therapies (and other therapies) designed for weight loss, as well as for patient-centered treatment optimization, the introduction of more objective and comprehensive ways of assessing muscle health (including accurate and meaningful assessments of muscle quantity, composition, function, mobility, and strength) is important for the substantial numbers of patients who will likely be taking these medications well into the future., Competing Interests: Dr Neeland has received honoraria, consulting, and speaker’s bureau fees and travel support from Boehringer-Ingelheim/Lilly Alliance, consulting and speaker’s bureau fees from Bayer Pharmaceuticals, and consulting fees from Novo Nordisk, and has participated in scientific advisory boards for Lilly, Boehringer Ingelheim, Novo Nordisk, and AMRA Medical. Dr Birkenfeld has received consulting fees from Novo Nordisk and Bayer, as well as research support from AstraZeneca, Boehringer Ingelheim, Novo Nordisk, Lilly, and Daiichi Sankyo, all given to Tübingen University. Dr Linge is an employee and shareholder of AMRA Medical AB, has received consulting and travel support from Eli Lilly, and has received speaker’s bureau fees and travel support from BioMarin.

Many studies have focused on the effects of small molecules, such as amino acids, on metabolism under hypoxia. Recent findings have indicated that phenylalanine levels were markedly elevated in adaptation to chronic hypoxia. This raises the possibility that phenylalanine treatment could markedly improve the hypoxic endurance. However, the importance of hypoxia-regulated phenylalanine is still unclear. This study investigates the role of phenylalanine in hypoxia adaptation using a hypoxic zebrafish model and multi-omics analysis. We found that phenylalanine-related metabolic pathways are significantly up-regulated under hypoxia, contributing to enhanced hypoxic endurance. Phenylalanine treatment reduced ROS levels, improved mitochondrial oxygen consumption rate (OCR), and extracellular acidification rate (ECAR) in hypoxic cells. Western blotting revealed increased phenylalanine uptake via L-type amino transporters (LAT1), activating the LKB1/AMPK signaling pathway. This activation up-regulated peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) and the Bcl-2/Bax ratio, while down-regulating uncoupling protein 2 (UCP2), thereby improving mitochondrial function under hypoxia. This is the first comprehensive multi-omics analysis to demonstrate phenylalanine's crucial role in hypoxia adaptation, providing insights for the development of anti-hypoxic drugs., (© 2024. The Author(s).)

Soil acidity is a divesting factor that restricts crop growth and productivity. Conversely, silicon nanomaterials (Si-NMs) have been praised as a blessing of modern agricultural intensification by overcoming the ecological barrier. Here, we performed a sequential study from seed germination to the yield performance of mustard ( Brassica campestris ) crops under acid-stressed conditions. The results showed that Si-NMs significantly improved seed germination and seedling growth under acid stress situations. These might be associated with increased antioxidant activity and the preserve ratio of GSH/GSSG and AsA/DHA, which is restricted by soil acidity. Moreover, Si-NMs in field regimes significantly diminished the acid-stress-induced growth inhibitions, as evidenced by increased net photosynthesis and biomass accumulations. Again, Si-NMs triggered all the critical metrics of crop productivity, including the seed oil content. Additionally, Si-NMs, upon dolomite supplementation, further triggered all the metrics of yields related to farming resilience. Therefore, the present study highlighted the crucial roles of Si-NMs in sustainable agricultural expansion and cropping intensification, especially in areas affected by soil acidity.

The toxicity of nanoplastics at environmentally relevant concentrations has received widespread attention in the context of global warming. Despite numerous studies on the impact of mean temperature (MT), the effects of daily temperature fluctuations (DTFs) on the ecotoxicity of nanoplastics remains largely unexplored. Moreover, the role of evolutionary adaptation in assessing long-term ecological risks is unclear. Here, we investigated the effects of polystyrene nanoplastics (5 μg L -1 ) on Daphnia magna under varying MT (20 °C and 24 °C) and DTFs (0 °C, 5 °C, and 10 °C). Capitalizing on a space-for-time substitution approach, we further assessed how local thermal adaptation affect the sensitivity of Daphnia to nanoplastics under global warming. Our results indicated that nanoplastics exposure in general reduced heartbeat rate, thoracic limb activity and feeding rate, and increased CytP450, ETS activity and Hgb concentrations. Higher MT and DTFs enhanced these effects. Notably, clones originating from their respective sites performed better under their native temperature conditions, indicating local thermal adaptation. Warm-adapted low-latitude D. magna showed stronger nanoplastics-induced increases in CytP450, ETS activity and Hgb concentrations under local MT 24 °C, while cold-adapted high-latitude D. magna showed stronger nanoplastics-induced decreases in heartbeat rate, thoracic limb activity and feeding rate under high MT than under low MT., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose of Review: Over the past decade, trophic gastrointestinal hormonal factors have been included in the intestinal rehabilitation programs for short bowel syndrome (SBS). Up today the only trophic factor approved for clinical practice is the glucagon-like peptide-2 (GLP-2) analogue, teduglutide. A literature review on the last 2-year data on GLP-2 analogues for the treatment of SBS in adults has been performed., Recent Findings: Several reports on real-world data on the efficacy and safety of teduglutide treatment for SBS, some case-reports on the use of teduglutide in non-SBS conditions as well as phase 2 trials on new GL-2 analogues on patients with SBS have been retrieved., Summary: Real-world data confirmed the teduglutide efficacy not only in weaning off IVS in accurately selected patients but also increased the alert on the risk of development of gastrointestinal polyps related to the drug; the impact of the therapy on patients' QoL deserves further studies and the cost-utility of the treatment is still uncertain. Some case reports highlighted the potential benefit of treatment with teduglutide in non-SBS gastrointestinal diseases, such as graft-versus-host disease, primary amyloidosis and refractory microscopic colitis. Phase 2 RCTs on safety and efficacy of two new long-acting GLP-2 analogues, glepaglutide and apraglutide, were published, and phase 3 RCTs have been completed., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Thiosemicarbazones and their metal complexes have been studied for their biological activities against bacteria, cancer cells and protozoa. Short-term in vitro treatment with one gold (III) complex (C3) and its salicyl-thiosemicarbazone ligand (C4) selectively inhibited proliferation of T. gondii . Transmission Electron Microscopy (TEM) detected transient structural alterations in the parasitophorous vacuole membrane and the tachyzoite cytoplasm, but the mitochondrial membrane potential appeared unaffected by these compounds. Proteins potentially interacting with C3 and C4 were identified using differential affinity chromatography coupled with mass spectrometry (DAC-MS). Moreover, long-term in vitro treatment was performed to investigate parasitostatic or parasiticidal activity of the compounds. DAC-MS identified 50 ribosomal proteins binding both compounds, and continuous drug treatments for up to 6 days caused the loss of efficacy. Parasite tolerance to both compounds was, however, rapidly lost in their absence and regained shortly after re-exposure. Proteome analyses of six T. gondii ME49 clones adapted to C3 and C4 compared to the non-adapted wildtype revealed overexpression of ribosomal proteins, of two transmembrane proteins involved in exocytosis and of an alpha/beta hydrolase fold domain-containing protein. Results suggest that C3 and C4 may interfere with protein biosynthesis and that adaptation may be associated with the upregulated expression of tachyzoite transmembrane proteins and transporters, suggesting that the in vitro drug tolerance in T. gondii might be due to reversible, non-drug specific stress-responses mediated by phenotypic plasticity.

Pharmacological approaches to induce N-methyl-d-aspartate receptor (NMDAR) hypofunction have been intensively used to understand the aetiology and pathophysiology of schizophrenia. Yet, the precise cellular and molecular mechanisms that relate to brain network dysfunction remain largely unknown. Here, we used a set of complementary approaches to assess the functional network abnormalities present in male mice that underwent a 7-day subchronic phencyclidine (PCP 10 mg/kg, subcutaneously, once daily) treatment. Our data revealed that pharmacological intervention with PCP affected cognitive performance and auditory evoked gamma oscillations in the prefrontal cortex (PFC) mimicking endophenotypes of some schizophrenia patients. We further assessed PFC cellular function and identified altered neuronal intrinsic membrane properties, reduced parvalbumin (PV) immunostaining and diminished inhibition onto L5 PFC pyramidal cells. A decrease in the strength of optogenetically-evoked glutamatergic current at the ventral hippocampus to PFC synapse was also demonstrated, along with a weaker shunt of excitatory transmission by local PFC interneurons. On a macrocircuit level, functional ultrasound measurements indicated compromised functional connectivity within several brain regions particularly involving PFC and frontostriatal circuits. Herein, we reproduced a panel of schizophrenia endophenotypes induced by subchronic PCP application in mice. We further recapitulated electrophysiological signatures associated with schizophrenia and provided an anatomical reference to critical elements in the brain circuitry. Together, our findings contribute to a better understanding of the physiological underpinnings of deficits induced by subchronic NMDAR antagonist regimes and provide a test system for characterization of pharmacological compounds., Competing Interests: Declaration of competing interest All authors are employees of Boehringer Ingelheim Pharma & Co. KG., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Brown adipose tissue (BAT) participates in thermogenesis and energy homeostasis. Studies on factors capable of influencing BAT function, such as a high-fat diet (HFD) or exposure to environmental pollutants, could be useful for finding metabolic targets for maintaining energy homeostasis. We evaluated the effect of chronic exposure to dichlorodiphenyldichloroethylene (DDE), the major metabolite of dichlorodiphenyltrichloroethane (DDT), and/or a HFD on BAT morphology, mitochondrial mass, dynamics, and oxidative stress in rats. To this end, male Wistar rats were treated for 4 weeks with a standard diet, or a HFD alone, or together with DDE. An increase in paucilocular adipocytes and the lipid droplet size were observed in HFD-treated rats, which was associated with a reduction in mitochondrial mass and in mitochondrial fragmentation, as well as with increased oxidative stress and upregulation of the superoxide dismutase-2. DDE administration mimics most of the effects induced by a HFD on BAT, and it aggravates the increase in the lipid droplet size when administered together with a HFD. Considering the known role of oxidative stress in altering BAT functionality, it could underlie the ability of both DDE and a HFD to induce similar metabolic adaptations in BAT, leading to reduced tissue thermogenesis, which can result in a predisposition to the onset of energy homeostasis disorders.

Despite the increased research efforts aimed at understanding iron-based conductive materials (CMs) for facilitating chain elongation (CE) to produce medium chain fatty acids (MCFAs), the impact of these materials on microbial community functions and the adaptation mechanisms to their biotoxicity remain unclear. This study found that the supply of zero-valent iron (ZVI) and magnetite enhanced the MCFAs carbon-flow distribution by 26 % and 52 %, respectively. Metagenomic analysis revealed the upregulation of fatty acid metabolism, pyruvate metabolism and ABC transporters with ZVI and magnetite. The predominant functional microorganisms were Massilibacterium and Tidjanibacter with ZVI, and were Petrimonas and Candidatus&#95;Microthrix with magnetite. Furthermore, it was demonstrated that CE microorganisms respond and adapt to the biotoxicity of iron-based CMs by adjusting Two-component system and Quorum sensing for the first time. In summary, this study provided a new deep-insight on the feedback mechanisms of CE microorganisms on iron-based CMs., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Daphnia galeata is a suitable model organism for investigating predator-induced defense. Genes and pathways exhibiting differential expression between fish kairomone-treated and untreated groups in D. galeata have been identified. However, understanding of the significance of alternative splicing, a crucial process of the regulation of gene expression in eukaryotes, to this mechanism remains limited. This study measured life-history traits and conducted short-read RNA sequencing and long-read isoform sequencing of two Korean D. galeata genotypes (KB1 and KE2) to uncover the genetic mechanism underlying their phenotypic plasticity under predation stress., Results: KB1 exhibited strategies to enhance fertility and decrease body length when exposed to fish kairomones, while KE2 deployed an adaptive strategy to increase body length. Full-length transcriptomes from KB1 and KE2 yielded 65,736 and 57,437 transcripts, respectively, of which 32 differentially expressed transcripts (DETs) were shared under predation stress across both genotypes. Prominent DETs common to both genotypes were related to energy metabolism and the immune system. Additionally, differential alternative splicing (DAS) events were detected in both genotypes in response to fish kairomones. DAS genes shared between both genotypes may indicate their significant role in the post-transcriptional stress response to fish predation. Calpain-3, involved in digestion and nutrient absorption, was identified as a DAS gene in both genotypes when exposed to fish kairomones. In addition, the gene encoding thymosin beta, which is related to growth, was found to be a statistically significant DAS only in KB1, while that encoding ultraspiracle protein, also associated with growth, was only identified in KE2. Moreover, transcripts encoding proteins such as EGF-like domain-containing protein, vitellogenin fused with superoxide dismutase, and others were identified overlapping between DAS events and DETs and potentially elucidating their association with the observed phenotypic variation in each genotype., Conclusions: Our findings highlight the crucial role of alternative splicing in modulating transcriptome landscape under predation stress in D. galeata, emphasizing the requirement for integrating gene expression and splicing analyses in evolutionary adaptation studies., (© 2024. The Author(s).)

Harsh environments in poorly perfused tumor regions may select for traits driving cancer aggressiveness. Here, we investigated whether tumor acidosis interacts with driver mutations to exacerbate cancer hallmarks. We adapted mouse organoids from normal pancreatic duct (mN10) and early pancreatic cancer (mP4, KRAS-G12D mutation, ± p53 knockout) from extracellular pH 7.4 to 6.7, representing acidic niches. Viability was increased by acid adaptation, a pattern most apparent in wild-type (WT) p53 organoids, and exacerbated upon return to pH 7.4. This led to increased survival of acid-adapted organoids treated with gemcitabine and/or erlotinib, and, in WT p53 organoids, acid-induced attenuation of drug effects. New genetic variants became dominant during adaptation, yet they were unlikely to be its main drivers. Transcriptional changes induced by acid and drug adaptation differed overall, but acid adaptation increased the expression of gemcitabine resistance genes. Thus, adaptation to acidosis increases cancer cell viability after chemotherapy., Competing Interests: Declaration of interests S.F.P. is a cofounder of SOLID Therapeutics., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Aims: As the interactions of alcohol and HIV/SIV infection and their impact on liver metabolic homeostasis remain to be fully elucidated, this study aimed to determine alcohol-mediated hepatic adaptations of metabolic pathways in SIV/ART-treated female rhesus macaques fed a nutritionally balanced diet., Methods: Macaques were administered chronic binge alcohol (CBA; 13-14 g ethanol/kg/week for 14.5 months; n = 7) or vehicle (VEH; n = 8) for 14.5 months. Livers were excised following an overnight fast. Gene and protein expression, enzymatic activity, and lipid content were determined using frozen tissue and histological staining was performed using paraffin-embedded tissue., Results: CBA/SIV macaques showed increased hepatic protein expression of electron transport Complex III and increased gene expression of glycolytic (phosphofructokinase and aldolase) and gluconeogenic (pyruvate carboxylase) enzymes and of genes involved in lipid turnover homeostasis (perilipin 1, peroxisome proliferator-activated receptor gamma, carbohydrate responsive binding protein, and acetyl-CoA carboxylase B) as compared to that of livers from the VEH/SIV group. Plasma triglyceride concentration had a significant positive association with liver triglyceride content in the CBA/SIV group., Conclusions: These results reflect CBA-associated alterations in expression of proteins and genes involved in glucose and lipid metabolism homeostasis without significant evidence of steatosis or dysglycemia. Whether these changes predispose to greater liver pathology upon consumption of a high fat/high sugar diet that is more aligned with dietary intake of PWH and/or exposure to additional environmental factors warrants further investigation., (© The Author(s) 2024. Medical Council on Alcohol and Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The aim of the current study was to investigate the effects of ingesting different dosages of caffeine (CAF) prior to plyometric jump training (PJT) on sport-related performance and physiological parameters in male basketball players. Twenty-four young athletes were randomly divided into 3 groups and performed 6 weeks of PJT while consuming 3 mg·kg -1 of body mass caffeine (CAF3, n = 8), 6 mg·kg -1 body mass caffeine (CAF6, n = 8) or placebo (PL; n = 8) one hour prior to each training session. Before and after the 6-week PJT, the players were evaluated for field-based basketball-specific performance measures (vertical jump, 20-m sprint, Illinois change of direction speed [CODS], and maximal strength) and lab-based physiological (aerobic capacity and anaerobic power) parameters. CAF3, CAF6, and PL groups demonstrated significant improvements in vertical jump (ES = 1.07, 1.45, and 1.1, respectively), 20-m sprint (ES = - 0.50, - 0.61, and - 0.36), change of direction performance (ES = - 1.22, - 1.26, and - 1.09), maximal strength (ES = 1.68, 2.29, and 1.17), maximum oxygen uptake (V̇O 2max ) (ES = 1.09, 1.59, and 0.92), and peak (ES = 1.82, 1.85, and 0.82) and average power output (ES = 1.39, 1.32, and 1.07) after 6 weeks of training. Comparative analysis of individual adaptive responses to training indicated that the CAF6 led to insignificantly greater effects in vertical jump (ES = 1.45), maximal strength (ES = 2.29), and V̇O 2max (ES = 1.59) with lower residuals in individual changes and lower coefficient of variations (CV) in mean group changes. Regarding sprint and CODS performance, both experimental groups indicated similar changes, residuals in individual changes, and CVs in mean group changes. Overall, consuming 6 mg·kg -1 body mass caffeine induces superior adaptations in aerobic fitness, anaerobic power, and sport-specific performance measures, with lower inter-individual variability in the adaptations and more homogenized changes over the training period., (© 2024. The Author(s).)

Advancements in precision oncology over the past decades have led to new therapeutic interventions, but the efficacy of such treatments is generally limited by an adaptive process that fosters drug resistance 1 . In addition to genetic mutations 2 , recent research has identified a role for non-genetic plasticity in transient drug tolerance 3 and the acquisition of stable resistance 4,5 . However, the dynamics of cell-state transitions that occur in the adaptation to cancer therapies remain unknown and require a systems-level longitudinal framework. Here we demonstrate that resistance develops through trajectories of cell-state transitions accompanied by a progressive increase in cell fitness, which we denote as the 'resistance continuum'. This cellular adaptation involves a stepwise assembly of gene expression programmes and epigenetically reinforced cell states underpinned by phenotypic plasticity, adaptation to stress and metabolic reprogramming. Our results support the notion that epithelial-to-mesenchymal transition or stemness programmes-often considered a proxy for phenotypic plasticity-enable adaptation, rather than a full resistance mechanism. Through systematic genetic perturbations, we identify the acquisition of metabolic dependencies, exposing vulnerabilities that can potentially be exploited therapeutically. The concept of the resistance continuum highlights the dynamic nature of cellular adaptation and calls for complementary therapies directed at the mechanisms underlying adaptive cell-state transitions., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Astaxanthin, a potent antioxidant found in marine organisms such as microalgae and krill, may offer ergogenic benefits to endurance athletes. Originally used in fish feed, astaxanthin has shown a greater ability to mitigate various reactive oxygen species and maintain the structural integrity of mitochondria compared to other exogenous antioxidants. More recent work has shown that astaxanthin may improve: (1) cycling time trial performance, (2) cardiorespiratory measures such as submaximal heart rate during running or cycling, (3) recovery from delayed-onset muscle soreness, and (4) endogenous antioxidant capacity such as whole blood glutathione within trained populations. In this review, the history of astaxanthin and its chemical structure are first outlined before briefly describing the various adaptations (e.g., mitochondrial biogenesis, enhanced endogenous antioxidant capacity, etc.) which take place specifically at the mitochondrial level as a result of chronic endurance training. The review then concludes with the potential additive effects that astaxanthin may offer in conjunction with endurance training for the endurance athlete and offers some suggested practical recommendations for athletes and coaches interested in supplementing with astaxanthin.

Key Message: AcEXPA1, an aluminum (Al)-inducible expansin gene, is demonstrated to be involved in carpetgrass (Axonopus compressus) root elongation under Al toxicity through analyzing composite carpetgrass plants overexpressing AcEXPA1. Aluminum (Al) toxicity is a major mineral toxicity that limits plant productivity in acidic soils by inhibiting root growth. Carpetgrass (Axonopus compressus), a dominant warm-season turfgrass widely grown in acidic tropical soils, exhibits superior adaptability to Al toxicity. However, the mechanisms underlying its Al tolerance are largely unclear, and knowledge of the functional genes involved in Al detoxification in this turfgrass is limited. In this study, phenotypic variation in Al tolerance, as indicated by relative root elongation, was observed among seventeen carpetgrass genotypes. Al-responsive genes related to cell wall modification were identified in the roots of the Al-tolerant genotype 'A58' via transcriptome analysis. Among them, a gene encoding α-expansin was cloned and designated AcEXPA1 for functional characterization. Observed Al dose effects and temporal responses revealed that Al induced AcEXPA1 expression in carpetgrass roots. Subsequently, an efficient and convenient Agrobacterium rhizogenes-mediated transformation method was established to generate composite carpetgrass plants with transgenic hairy roots for investigating AcEXPA1 involvement in carpetgrass root growth under Al toxicity. AcEXPA1 was successfully overexpressed in the transgenic hairy roots, and AcEXPA1 overexpression enhanced Al tolerance in composite carpetgrass plants through a decrease in Al-induced root growth inhibition. Taken together, these findings suggest that AcEXPA1 contributes to Al tolerance in carpetgrass via root growth regulation., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Excess of selenium (Se) in aquatic ecosystems has necessitated thorough investigations into the effects/consequences of this metalloid on the autochthonous organisms exposed to it. The molecular details of Se-mediated adaptive response remain unknown in cyanobacteria. This study aims to uncover the molecular mechanisms driving the divergent physiological responses of cyanobacteria on exposure to selenate [Se(VI)] or selenite [Se(IV)], the two major water-soluble oxyanions of Se. The cyanobacterium, Anabaena PCC 7120, withstood 0.4 mM of Se(VI), whereas even 0.1 mM of Se(IV) was detrimental, affecting photosynthesis and enhancing endogenous ROS. Surprisingly, Anabaena pre-treated with Se(VI), but not Se(IV), showed increased tolerance to oxidative stress mediated by H 2 O 2 /methyl viologen. RNA-Seq analysis showed Se(VI) to elevate transcription of genes encoding anti-oxidant proteins and Fe-S cluster biogenesis, whereas the photosynthesis-associated genes, which were mainly downregulated by Se(IV), remained unaffected. Specifically, the content of typical 2-Cys-Prx (Alr4641), a redox-maintaining protein in Anabaena, was elevated with Se(VI). In comparison to the wild-type, the Anabaena strain over-expressing the Alr4641 protein (An4641+) showed enhanced tolerance to Se(VI) stress, whereas the corresponding knockdown-strain (KD4641) was sensitive to this stressor. Incidentally, among these strains, only An4641+ was better protected from the ROS-mediated damage caused by high dose of Se(VI). These results suggest that altering the content of the antioxidant protein 2-Cys-Prx, could be a potential strategy for modulating resistance to selenate. Thus, involvement of oxidative stress machinery appears to be the major determinant, responsible for the contrasting physiological differences observed in response to selenate/selenite in cyanobacteria., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Soil contamination with arsenic (As) can cause phytotoxicity and reduce crop yield. The mechanisms of As toxicity and tolerance are not fully understood. In this study, we used a forward genetics approach to isolate a rice mutant, ahs1, that exhibits hypersensitivity to both arsenate and arsenite. Through genomic resequencing and complementation tests, we identified OsLPD1 as the causal gene, which encodes a putative lipoamide dehydrogenase. OsLPD1 was expressed in the outer cell layer of roots, root meristem cells, and in the mesophyll and vascular tissues of leaves. Subcellular localization and immunoblot analysis demonstrated that OsLPD1 is localized in the stroma of plastids. In vitro assays showed that OsLPD1 exhibited lipoamide dehydrogenase (LPD) activity, which was strongly inhibited by arsenite, but not by arsenate. The ahs1 and OsLPD1 knockout mutants exhibited significantly reduced NADH/NAD + and GSH/GSSG ratios, along with increased levels of reactive oxygen species and greater oxidative stress in the roots compared with wild-type (WT) plants under As treatment. Additionally, loss-of-function of OsLPD1 also resulted in decreased fatty acid concentrations in rice grain. Taken together, our finding reveals that OsLPD1 plays an important role for maintaining redox homeostasis, conferring tolerance to arsenic stress, and regulating fatty acid biosynthesis in rice., (© 2024 The Authors New Phytologist © 2024 New Phytologist Foundation.)

The chemical arms race between plants and insects is foundational to the generation and maintenance of biological diversity. We asked how the evolution of a novel defensive compound in an already well-defended plant lineage impacts interactions with diverse herbivores. Erysimum cheiranthoides (Brassicaceae), which produces both ancestral glucosinolates and novel cardiac glycosides, served as a model. We analyzed gene expression to identify cardiac glycoside biosynthetic enzymes in E. cheiranthoides and characterized these enzymes via heterologous expression and CRISPR/Cas9 knockout. Using E. cheiranthoides cardiac glycoside-deficient lines, we conducted insect experiments in both the laboratory and field. EcCYP87A126 initiates cardiac glycoside biosynthesis via sterol side-chain cleavage, and EcCYP716A418 has a role in cardiac glycoside hydroxylation. In EcCYP87A126 knockout lines, cardiac glycoside production was eliminated. Laboratory experiments with these lines revealed that cardiac glycosides were highly effective defenses against two species of glucosinolate-tolerant specialist herbivores, but did not protect against all crucifer-feeding specialist herbivores in the field. Cardiac glycosides had lesser to no effect on two broad generalist herbivores. These results begin elucidation of the E. cheiranthoides cardiac glycoside biosynthetic pathway and demonstrate in vivo that cardiac glycoside production allows Erysimum to escape from some, but not all, specialist herbivores., (© 2024 The Authors New Phytologist © 2024 New Phytologist Foundation.)

To study the heavy metal accumulation and its impact on insect exterior and chromosome morphology, and reveal the molecular mechanism of insects adapting to long-term heavy metal compound pollution habitats, this study, in the Diaojiang river basin, which has been polluted by heavy metals(HMs) for nearly a thousand years, two Eucriotettix oculatus populations was collected from mining and non-mining areas. It was found that the contents of 7 heavy metals (As, Cd, Pb, Zn, Cu, Sn, Sb) in E. oculatus of the mining area were higher than that in the non-mining 1-11 times. The analysis of morphology shows that the external morphology, the hind wing type and the chromosomal morphology of E. oculatus are significant differences between the two populations. Based on the heavy metal accumulation，morphological change, and stable population density, it is inferred that the mining area population has been affected by heavy metals and has adapted to the environment of heavy metals pollution. Then, by analyzing the transcriptome of the two populations, it was found that the digestion, immunity, excretion, endocrine, nerve, circulation, reproductive and other systems and lysosomes, endoplasmic reticulum and other cell structure-related gene expression were suppressed. This shows that the functions of the above-mentioned related systems of E. oculatus are inhibited by heavy metal stress. However, it has also been found that through the significant up-regulation of genes related to the above system, such as ATP2B, pepsin A, ubiquitin, AQP1, ACOX, ATPeV0A, SEC61A, CANX, ALDH7A1, DLD, aceE, Hsp40, and catalase, etc., and the down-regulation of MAPK signalling pathway genes, can enhanced nutrient absorption, improve energy metabolism, repair damaged cells and degrade abnormal proteins, maintain the stability of cells and systems, and resist heavy metal damage so that E. oculatus can adapt to the environment of heavy metal pollution for a long time., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Stomatal operation is crucial for optimising plant water and gas exchange and represents a major trait conferring abiotic stress tolerance in plants. About 56% of agricultural land around the globe is classified as acidic, and Al toxicity is a major limiting factor affecting plant performance in such soils. While most of the research work in the field discusses the impact of major abiotic stresses such as drought or salinity on stomatal operation, the impact of toxic metals and, specifically aluminium (Al) on stomatal operation receives much less attention. We aim to fill this knowledge gap by summarizing the current knowledge of the adverse effects of acid soils on plant stomatal development and operation. We summarised the knowledge of stomatal responses to both long-term and transient Al exposure, explored molecular mechanisms underlying plant adaptations to Al toxicity, and elucidated regulatory networks that alleviate Al toxicity. It is shown that Al-induced stomatal closure involves regulations of core stomatal signalling components, such as ROS, NO, and CO 2 and key elements of ABA signalling. We also discuss possible targets and pathway to modify stomatal operation in plants grown in acid soils thus reducing the impact of Al toxicity on plant growth and yield., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Soil acidity is a global issue; soils with pH <4.5 are widespread in Europe. This acidity adversely affects nutrient availability to plants; pH levels <5.0 lead to aluminum (Al 3+ ) toxicity, a significant problem that hinders root growth and nutrient uptake in faba bean (Vicia faba L.) and its symbiotic relationship with Rhizobium. However, little is known about the specific traits and tolerant genotypes among the European faba beans. This study aimed to identify response traits associated with tolerance to root zone acidity and Al 3+ toxicity and potentially tolerant genotypes for future breeding efforts. Germplasm survey was conducted using 165 genotypes in a greenhouse aquaponics system. Data on the root and shoot systems were collected. Subsequently, 12 genotypes were selected for further phenotyping in peat medium, where data on physiological and morphological parameters were recorded along with biochemical responses in four selected genotypes. In the germplasm survey, about 30% of genotypes showed tolerance to acidity and approximately 10% exhibited tolerance to Al 3+ , while 7% showed tolerance to both. The phenotyping experiment indicated diverse morphological and physiological responses among treatments and genotypes. Acid and Al 3+ increased proline concentration. Interaction between genotype and environment was observed for ascorbate peroxidase activity, malondialdehyde, and proline concentrations. Genomic markers associated with acidity and acid+Al 3+ -toxicity tolerances were identified using GWAS analysis. Four faba bean genotypes with varying levels of tolerance to acidity and Al 3+ toxicity were identified., (© 2024 The Author(s). Physiologia Plantarum published by John Wiley & Sons Ltd on behalf of Scandinavian Plant Physiology Society.)

A stressor can trigger lasting adaptations that contribute to neuropsychiatric disorders. Predator odor (TMT) exposure is an innate stressor that may activate the metabotropic glutamate receptor 3 (mGlu 3 ) to produce stress adaptations. To evaluate functional involvement, the mGlu 3 negative allosteric modulator (NAM, VU6010572; 3 mg/kg, i.p.) was administered before TMT exposure in male, Long Evans rats. Two weeks after, rats underwent context re-exposure, elevated zero maze (ZM), and acoustic startle (ASR) behavioral tests, followed by RT-PCR gene expression in the insular cortex and bed nucleus of the stria terminalis (BNST) to evaluate lasting behavioral and molecular adaptations from the stressor. Rats displayed stress-reactive behaviors in response to TMT exposure that were not affected by VU6010572. Freezing and hyperactivity were observed during the context re-exposure, and mGlu 3 -NAM pretreatment during stressor prevented the context freezing response. TMT exposure did not affect ZM or ASR measures, but VU6010572 increased time spent in the open arms of the ZM and ASR habituation regardless of stressor treatment. In the insular cortex, TMT exposure increased expression of mGlu (Grm3, Grm5) and NMDA (GriN2A, GriN2B, GriN2C, GriN3A, GriN3B) receptor transcripts, and mGlu 3 -NAM pretreatment blocked GriN3B upregulation. In the BNST, TMT exposure increased expression of GriN2B and GriN3B in vehicle-treated rats, but decreased expression in the mGlu 3 -NAM group. Similar to the insular cortex, mGlu 3 -NAM reversed the stressor-induced upregulation of GriN3B in the BNST. mGlu 3 -NAM also upregulated GriN2A, GriN2B, GriN3B and Grm2 in the control group, but not the TMT group. Together, these data implicate mGlu 3 receptor signaling in some lasting adaptations of predator odor stressor and anxiolytic-like effects., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Drought stress tolerance is a complex trait regulated by multiple factors. Here, we demonstrate that the miRNA160-Auxin Response Factor 17 (ARF17)-HYPONASTIC LEAVES 1 module is crucial for apple (Malus domestica) drought tolerance. Using stable transgenic plants, we found that drought tolerance was improved by higher levels of Mdm-miR160 or MdHYL1 and by decreased levels of MdARF17, whereas reductions in MdHYL1 or increases in MdARF17 led to greater drought sensitivity. Further study revealed that modulation of drought tolerance was achieved through regulation of drought-responsive miRNA levels by MdARF17 and MdHYL1; MdARF17 interacted with MdHYL1 and bound to the promoter of MdHYL1. Genetic analysis further suggested that MdHYL1 is a direct downstream target of MdARF17. Importantly, MdARF17 and MdHYL1 regulated the abundance of Mdm-miR160. In addition, the Mdm-miR160-MdARF17-MdHYL1 module regulated adventitious root development. We also found that Mdm-miR160 can move from the scion to the rootstock in apple and tomato (Solanum lycopersicum), thereby improving root development and drought tolerance of the rootstock. Our study revealed the mechanisms by which the positive feedback loop of Mdm-miR160-MdARF17-MdHYL1 influences apple drought tolerance., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Drought has become one of the environmental threats to agriculture and food security. Applications of melatonin (MT) serve as an effective way to alleviate drought stress, but the underlying mechanism remains poorly understood. Here, we found that foliar spray of 100-µM MT greatly mitigated the severe drought stress-induced damages in rice seedlings, including improved survival rates, enhanced antioxidant system, and adjusted osmotic balance. However, mutation of the suppressor of the G2 allele of skp1 ( OsSGT1 ) and ABSCISIC ACID INSENSITIVE 5 ( OsABI5 ) abolished the effects of MT. Furthermore, the upregulated expression of OsABI5 was detected in wild type (WT) under drought stress, irrespective of MT treatment, whereas OsABI5 was significantly downregulated in sgt1 and sgt1abi5 mutants. In contrast, no change of the OsSGT1 expression level was detected in abi5 . Moreover, mutation of OsSGT1 and OsABI5 significantly suppressed the expression of genes associated with the antioxidant system. These results suggested that the functions of OsSGT1 in the MT-mediated alleviation of drought stress were associated with the ABI5-mediated signals. Collectively, we demonstrated that OsSGT1 was involved in the drought response of rice and that melatonin promoted SGT1-involved signals to ameliorate drought stress adaption.

Low temperature during the vegetative stage depresses rice tillering. Zinc (Zn) can promote rice tiller growth and improve plant resistance to abiotic stress. Consequently, Zn application after low temperature might be an effective approach to promote rice tiller recovery. A water culture experiment with treatments of two temperatures (12 °C and 20 °C) and three Zn concentrations (0.08 μM, 0.15 μM and 0.31 μM ZnSO 4 ·7H 2 O) was conducted to determine by analyzing rice tiller growth, nutrient absorption and hormones metabolism. The results showed that low temperature reduced rice tiller numbers and leaf age, decreased as well. Increasing Zn application after low temperature could enhance not only rice tiller growth rate but also N metabolism and tillering recovery, and correlation analysis showed a significantly positive correlation between tiller increment and Zn and N accumulation after low temperature. In addition, higher cytokinin (CTK)/auxin (IAA) ratio was maintained by promoted synthesis of CTK and IAA as well as enhanced IAA transportation from tiller buds to other parts with increased Zn application after cold stress, which resulted in accelerated germination and growth of tiller buds. These results highlighted that Zn application after low temperature promoted rice tiller recovery by increasing N and Zn accumulation and maintaining hormones balance., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Recent reports have implied that aberrant biochemical processes in the brain are frequently accompanied by subtle shifts in the cellular epigenetic profile that might underlie the pathogenic progression of psychiatric disorders. The aim of the present study was to examine the effect of trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, on the emotional abnormality induced by maladaptation to stress in mice. Mice were exposed to repeated restraint stress for 240 min/day for 14 days. We applied dosing schedules. In one schedule, from the 3rd day of stress exposure, mice were treated with TSA (1650 μM/4 μL, i.c.v.) immediately after the daily exposure to restraint stress. In the other schedule, from the 1st day of stress exposure, mice were treated with TSA 2 h before exposure to restraint stress. After the final exposure to restraint stress, the emotionality of mice was evaluated using the hole-board test. Mice that were exposed to restraint stress for 240 min/day for 14 days showed a decrease in head-dipping behavior. This decreased emotionality observed in stress-maladaptive mice was significantly recovered by chronic treatment with TSA 2 h before daily exposure to restraint stress, which confirmed the development of stress adaptation. On the other hand, no such stress adaptation was observed under chronic treatment with TSA immediately after daily stress exposure. A biochemical study showed that tryptophan hydroxylase, the rate-limiting enzyme in serotonin (5-HT) synthesis, was increased in midbrain containing raphe nuclei obtained from stress-adapted mice that were chronically treated with TSA 2 h before daily stress exposure. These findings suggest that an HDAC inhibitor may have a beneficial effect on stress adaptation by affecting 5-HT neural function in the brain and alleviate the emotional abnormality under conditions of excessive stress., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aluminum (Al) toxicity is the main factor limiting plant growth and the yield of cereal crops in acidic soils. Al-induced oxidative stress could lead to the excessive accumulation of reactive oxygen species (ROS) and aldehydes in plants. Aldehyde dehydrogenase ( ALDH ) genes, which play an important role in detoxification of aldehydes when exposed to abiotic stress, have been identified in most species. However, little is known about the function of this gene family in the response to Al stress. Here, we identified an ALDH gene in maize, ZmALDH , involved in protection against Al-induced oxidative stress. Al stress up-regulated ZmALDH expression in both the roots and leaves. The expression of ZmALDH only responded to Al toxicity but not to other stresses including low pH and other metals. The heterologous overexpression of ZmALDH in Arabidopsis increased Al tolerance by promoting the ascorbate-glutathione cycle, increasing the transcript levels of antioxidant enzyme genes as well as the activities of their products, reducing MDA, and increasing free proline synthesis. The overexpression of ZmALDH also reduced Al accumulation in roots. Taken together, these findings suggest that ZmALDH participates in Al-induced oxidative stress and Al accumulation in roots, conferring Al tolerance in transgenic Arabidopsis .

Plant plasma membrane H+-ATPases and Ca2+-ATPases maintain low cytoplasmic concentrations of H+ and Ca2+, respectively, and are essential for plant growth and development. These low concentrations allow plasma membrane H+-ATPases to function as electrogenic voltage stats, and Ca2+-ATPases as "off" mechanisms in Ca2+-based signal transduction. Although these pumps are autoregulated by cytoplasmic concentrations of H+ and Ca2+, respectively, they are also subject to exquisite regulation in response to biotic and abiotic events in the environment. A common paradigm for both types of pumps is the presence of terminal regulatory (R) domains that function as autoinhibitors that can be neutralized by multiple means, including phosphorylation. A picture is emerging in which some of the phosphosites in these R domains appear to be highly, nearly constantly phosphorylated, whereas others seem to be subject to dynamic phosphorylation. Thus, some sites might function as major switches, whereas others might simply reduce activity. Here, we provide an overview of the relevant transport systems and discuss recent advances that address their relation to external stimuli and physiological adaptations., (© American Society of Plant Biologists 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)