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Plasmodium vivax is the most widespread malaria parasite affecting humans, and its eradication is challenging due to the spread of drug-resistant parasites and their ability to remain in liver as a dormant stage. These parasites invade and multiply extensively within hepatocytes and erythrocytes in the host, relying on nutrient acquisition for their growth and replication. A promising new treatment aimed at targeting P. vivax involves blocking cationic amino acid uptake, which is a biological source of nutrients for the parasite. Novel Putative Transporter 1 (NPT1), identified as a cationic amino acid transporter in Apicomplexan, has a homologue in Plasmodium species known as apicomplexan amino acid transporter 8 (ApiAT8). This study focuses on P. vivax ApiAT8 to understand its precise role. PvApiAT8 was expressed in Xenopus laevis oocytes and shown to selectively uptake cationic amino acids. The uptake activity of [3H] L-arginine was shown to depend on PvApiAT8 expression time and substrate incubation time. PvApiAT8 was sodium-independent and functioned at pH levels between 6.5 and 8.5, with no efflux activity observed. Kinetic analysis showed saturable uptake for L-arginine consistent with Michaelis-Menten kinetics, with a Km of 1.5 ± 0.3 µM and a Vmax of 25.0 ± 4.8 pmol/oocyte/hr. Inhibition assays further confirmed its selectivity for cationic amino acids such as L-arginine, L-lysine, L-histidine, and L-ornithine. Sequence and structural analyses revealed a conserved binding pocket for cationic amino acids in Plasmodium species, distinct from that in Toxoplasma gondii NPT1. These findings highlight the potential of targeting PvApiAT8 in developing new treatments for P. vivax malaria. [ABSTRACT FROM AUTHOR]

The fecundity of Nilaparvata lugens (brown planthopper) is influenced by trehalase (TRE). To investigate the mechanism by which trehalose affects the reproduction of N. lugens, we conducted a comparative transcriptomic and metabolomic analysis of the ovaries of N. lugens following injection with dsTREs and validamycin (a TRE inhibitor). The results revealed that 844 differentially expressed genes (DEGs) were identified between the dsGFP and dsTREs injection groups, with 317 up-regulated genes and 527 down-regulated genes. Additionally, 1451 DEGs were identified between the water and validamycin injection groups, with 637 up-regulated genes and 814 down-regulated genes. The total number of DEGs identified between the two comparison groups was 236. The overlapping DEGs were implicated in various biological processes, including protein metabolism, fatty acid metabolism, AMPK signaling, mTOR signaling, insulin/insulin-like growth factor signaling (IIS), the tricarboxylic acid (TCA) cycle, oxidative phosphorylation, and the cellular process of meiosis in oocytes. These results suggest that the inhibition of TRE expression may lead to alterations in ovarian nutrient and energy metabolism by modulating glucose transport and affecting amino acid metabolic pathways. These alterations may influence the reproduction of N. lugens by modulating reproductive regulatory signals. These findings provide robust evidence supporting the mechanism through which trehalase inhibition reduces the reproductive capacity of N. lugens. [ABSTRACT FROM AUTHOR]

Bacterial cytokinesis begins with polymerization of the tubulin homologue FtsZ into a ring-like structure at midcell, the Z-ring, which recruits the late cell division proteins that synthesize the division septum. Assembly of FtsZ is carefully regulated and supported by a dozen conserved cell division proteins. Generally, these proteins are not essential, but removing more than one is in many cases lethal. Therefore, it is still not fully clear how the different protein components contribute to cell division, and whether there is a minimal set of proteins that can execute cell division. In this study, we tried to find the minimal set of proteins that is required to establish an active Z-ring in the model bacterium Bacillus subtilis. By making use of known suppressor mutations we were able to find a gene deletion route that eventually enabled us the remove eight conserved cell division proteins: ZapA, MinC, MinJ, UgtP, ClpX, Noc, EzrA and FtsA. Only FtsZ and its membrane anchor SepF appeared to be required for Z-ring formation. Interestingly, SepF is also the FtsZ anchor in archaea, and both proteins date back to the Last Universal Common Ancestor (LUCA). Viability of the multiple deletion mutant was not greatly affected, although the frequency of cell division was considerably reduced. Whole genome sequencing suggested that the construction of this minimal divisome strain was also possible due to the accumulation of suppressor mutations. After extensive phenotypic testing of these mutations, we found an unexpected cell division regulation function for the branched chain amino acid transporter BraB, which may be related to a change in fatty acid composition. The implications of these findings for the role of SepF, and the construction of a minimal cell division machinery are discussed. Author summary: One of the key aims of synthetic biology is the construction of a minimal cell. Since bacteria are the simplest life forms, they are the preferred blueprint for such a cell. However, a functional synthetic cell needs to be able to divide, and we still do not know what set of proteins are minimally necessary for bacterial cell division. This also hampers a full mechanistic understanding of this crucial process. In this study we tried to find the minimal set of proteins required for cell division in the model bacterium Bacillus subtilis, following a specific stepwise gene deletion protocol. Eventually, we were able to remove 8 conserved cell division related proteins and found that for the first step of the assembly of the cell division machinery, only two proteins are necessary, SepF and FtsZ. This surprising finding provides new functional insights into the bacterial cell division process, a blueprint for a synthetic minimal cell division protein set, and in addition, the gene deletion process also revealed a previously unknown cell division regulation activity for the conserved amino acid transport protein BraB. [ABSTRACT FROM AUTHOR]

Introduction: The growth of evergreen fruit trees is influenced by the interaction of soil nitrogen (N) and leaf amino acid contents. However, information on free amino acid contents in leaves of fruiting and non-fruiting branches during long-term N fertilizer application remains scarce. Methods: Here, a four-year field experiment (2018-2021) in a citrus orchard revealed consistently lower total N and amino acid contents in leaves of fruiting compared to non-fruiting branches. Results and discussion: Appropriate N fertilizer application increased free amino acid and total N contents in leaves of both types of branches and fruits, but excessive amounts led to decreases. Correlation analysis showed that, in the early stage of fruit development, leaves on both types of branches can meet the N requirements of the fruit (R²=0.77 for fruiting, R²=0.82 for non-fruiting). As fruits entered the swelling stage, a significant positive correlation emerged between fruiting branch leaves and fruit total N content (R²=0.68), while the R² for leaves on non-fruiting branches dropped to 0.47, indicating a shift in N supply towards leaves on fruiting branches. Proline and arginine are the most abundant amino acids in these leaves. At fruit maturity, these amino acids account for more than half of the total amino acids in the fruit (29.0% for proline and 22.2% for arginine), highlighting their crucial role in fruit development. Further research is needed to investigate amino acid transport and distribution mechanisms between citrus leaves and fruits. [ABSTRACT FROM AUTHOR]

Simple Summary: Low-protein (LPRO) diets provide benefits such as reduced feed costs and improved utilization. However, the necessary nutritional data for optimizing these diets are incomplete, and formulation techniques are still developing. Moreover, there is no consensus on the impact of low-protein diets with balanced amino acids on production performance. This study examined the impact of protease and Bacillus coagulans on broilers fed LPRO diets, finding that these additives can counteract the negative effects by increasing serum amino acids, upregulating transporter genes, enhancing intestinal barriers, and improving cecal microbiota, offering a basis for promoting LPRO feeds in broiler production. Low-protein (LPRO) diets can effectively reduce feed costs and decrease environmental pollution, making them an important pathway to enhance the sustainability of livestock production. However, they may have adverse effects on the growth performance of broiler chickens, which has limited their widespread application. This study aims to explore the impact of adding protease (PRO) to LPRO diets on the growth performance of broiler chickens, especially under conditions with or without the presence of Bacillus coagulans (BC), in order to provide theoretical support for the scientific application and promotion of LPRO feeds. We selected 432 one-day-old broiler chickens and divided them into four treatment groups, which were fed with the control (CON) diet, the LPRO diet, the PRO diet (LPRO diet with added protease), and the PAB diet (PRO diet with added BC). The LPRO group demonstrated decreased growth performance while both PRO and PAB diets resulted in a significant increase (p < 0.05). Both PRO and PAB diets significantly enhanced the expression of amino acid transport genes and tight junction genes (p < 0.05) and optimized the composition of the intestinal microbiota. Overall, LPRO diets have a detrimental effect on the growth of broiler chickens, while the PRO and PAB diets effectively counteract these negative effects by improving protein digestion, amino acid absorption, and intestinal health. [ABSTRACT FROM AUTHOR]

Faba bean (Vicia faba L.) is a valuable ingredient in plant-based foods such as meat and dairy analogues. However, its typical taste and aroma are considered off-flavours in these food applications, representing a bottleneck during processing. Breeding is needed to develop varieties with minimal off-flavours and high protein content. The genetic regulation of these traits is underexplored. To dissect their genetic architecture, we performed a genome-wide association study (GWAS). A total of 245 faba bean accessions (the CGN population) were genotyped using the 90K-SPET targeted assay. These accessions were phenotyped in 2021 and 2022 in the Netherlands for protein, oil, fatty acids, lipid-derived products, phenolic acids, flavonoids, and tannins. The CGN population showed large phenotypic variation and moderate-to-high narrow-sense heritability for most traits. The growing environment significantly affected all traits, with trait-specific genotype-by-year (GxY) interactions. Condensed tannins and fatty acids were the most stable across the two years and had the highest heritability estimates (h2 > 0.6). GWAS identified a total of 148 single nucleotide polymorphisms (SNPs) loci in 2021 and 167 in 2022. Key candidate regulators included genes involved in lipid biosynthesis (ATS2, KAS, LPP), amino acid transport (CAT4) for protein storage, zero tannins locus-1 (zt-1), and regulators of the phenylpropanoid pathway, such as a shikimate kinase gene and transcription factors bHLH137-like and MYB. These results pave the way for validation studies and biotechnological applications to improve the quality of faba bean-based foods. [ABSTRACT FROM AUTHOR]

UMAMIT proteins have been known as key players in amino acid transport. In Arabidopsis, functions of several UMAMITs have been characterized, but their precise mechanism, evolutionary history and functional divergence remain elusive. In this study, we conducted phylogenetic analysis of the UMAMIT gene family across key species in the evolutionary history of plants, ranging from algae to angiosperms. Our findings indicate that UMAMIT proteins underwent a substantial expansion from algae to angiosperms, accompanied by the stabilization of the EamA (the main domain of UMAMIT) structure. Phylogenetic studies suggest that UMAMITs may have originated from green algae and be divided into four subfamilies. These proteins first diversified in bryophytes and subsequently experienced gene duplication events in seed plants. Subfamily I was potentially associated with amino acid transport in seeds. Regarding subcellular localization, UMAMITs were predominantly localized in the plasma membrane and chloroplasts. However, members from clade 8 in subfamily III exhibited specific localization in the tonoplast. These members may have multiple functions, such as plant disease resistance and root development. Furthermore, our protein structure prediction revealed that the four-helix bundle motif is crucial in controlling the UMAMIT switch for exporting amino acid. We hypothesize that the specific amino acids in the amino acid binding region determine the type of amino acids being transported. Additionally, subfamily II contains genes that are specifically expressed in reproductive organs and roots in angiosperms, suggesting neofunctionalization. Our study highlights the evolutionary complexity of UMAMITs and underscores their crucial role in the adaptation and diversification of seed plants. [ABSTRACT FROM AUTHOR]

Amino acids in wine grapes function as precursors for various secondary metabolites and play a vital role in plant growth, development, and stress resistance. The amino acid/auxin permease (AAAP) genes encode a large family of transporters; however, the identification and function of the AAAP gene family in grapes remain limited. Consequently, we conducted a comprehensive bioinformatics analysis of all AAAP genes in grapes, encompassing genome sequence analysis, conserved protein domain identification, chromosomal localization, phylogenetic relationship analysis, and gene expression profiling. This study identified 60 VvAAAP genes, distributed on 14 chromosomes and classified into eight subfamilies. Microarray and transcriptome data revealed that most VvAAAP genes decrease during development, but VvAAAP7 and VvAAAP33 gradually increase. VvAAAP23 and VvAAAP46 exhibited significantly higher expression levels, while VvAAAP30 demonstrated lower expression when subjected to salt and drought stress. VvAAAP genes exhibited diverse expression patterns, suggesting that the AAAP gene family possesses both diversity and specific functions in grapes. Furthermore, the expression patterns of VvAAAP genes analyzed by RT-qPCR facilitate further investigation into the biological functions of individual genes in different tissues. These findings provide valuable insights into the continued analysis of the AAAP gene family's functions in grapes. [ABSTRACT FROM AUTHOR]

Background: Pear black spot is caused by Alternaria tenuissima. It is one of the diseases of concern limiting pear production worldwide. Existing cultivation methods and fungicides are not sufficient to control early blight. Therefore, the aim of this study was to isolate and characterize two strains of Streptomyces and evaluate their potential for biological control of crop diseases caused by Alternaria tenuissima while promoting plant growth. It enriches the resources of biocontrol strains. Methods: In this study, the genetic background of the strain was elucidated through 16S rRNA gene analysis and multiphase taxonomic identification methods. The metabolic potential of the strain was assessed using a variety of approaches, including antiSMASH, COG, and KEGG databases, RGI tools, as well as the scanning of CAZY and plant-promoting genes. The biocontrol potential of the strain was further substantiated through a combination of plate experiments, gene cluster biopathway resolution and mass spectrometry validation of metabolites. Finally, the biocontrol efficacy of the strain was confirmed through fruit control experiments. Results: The study identified the potential new species status of the strains. Strain TRM 76130 exhibited a gene size of 5.94 Mbp and a G + C content of 73.65%, while strain TRM 76172 had a gene size of 8.30 Mbp and a G + C content of 71.38%. Both strains contained genes related to amino acid transport and metabolism, along with several CAZY genes and 19 plant growth factors. The resistance genes of strain TRM 76172 were classified as macrolides, and genomic prediction revealed the biosynthetic pathway of the active compound Candidin. Mass spectrometry analysis indicated that strains TRM 76172 and TRM 76130 contained the active compounds amphotericin A and daptomycin, respectively. The pear assays demonstrated that both strains of Streptomyces were capable of reducing the symptoms of pear black spot. Conclusion: The present study concludes that strains TRM76172 and TRM76130 possess significant potential to control Alternaria tenuissima and promote plant growth, thereby enriching the biocontrol fungal library. [ABSTRACT FROM AUTHOR]

Amino acids are the primary form of nitrogen utilization in higher plants, mainly transported by amino acid transporters. In this study, we analyzed the natural variation of amino acid transporter-like 4 (OsATL4) in rice germplasm resources, identified its spatiotemporal expression characteristics, determined its substrate transport, and validated its function using transgenic plants. We found that the promoter sequence of OsATL4 varied across 498 rice varieties. The expression level of OsATL4 was higher in japonica rice, which was negatively correlated with tiller number and grain yield. OsATL4 was highly expressed in the basal part, leaf sheath, stem, and young panicle, with its two splicing variants localized to the cell membrane. OsATL4a (the long splicing variant) had a high affinity for transporting Ser, Leu, Phe, and Thr, while OsATL4b (the short splicing variant) had a high affinity for transporting Ser, Leu, and Phe. Blocking OsATL4 promoted axillary bud outgrowth, rice tillering, and grain yield, whereas overexpression lines exhibited the opposite phenotype. Exogenous application of low concentrations of Ser promoted axillary bud outgrowth in overexpression lines, while high concentrations of Ser inhibited it. Conversely, the mutant lines showed the opposite response. Altered expression of OsATL4 might affect the expression of genes in nitrogen, auxin, and cytokinin pathways. We propose that two splicing variants of OsATL4 negatively regulate rice tillering and yield by mediating the transport of amino acids, making it a significant target for high-yield rice breeding. [ABSTRACT FROM AUTHOR]

Background: Soil microbes play a vital role in the ecosystem as they are able to carry out a number of vital tasks. Additionally, metagenomic studies offer valuable insights into the composition and functional potential of soil microbial communities. Furthermore, analyzing the obtained data can improve agricultural restoration practices and aid in developing more effective environmental management strategies. Methodology: In November 2023, sandy soil samples were collected from ten sites of different geographical areas surrounding natural lakes and artificial water points in the Tubaiq conservation area of King Salman Bin Abdulaziz Royal Natural Reserve (KSRNR), Saudi Arabia. In addition, genomic DNA was extracted from the collected soil samples, and 16S rRNA sequencing was conducted using high-throughput Illumina technology. Several computational analysis tools were used for gene prediction and taxonomic classification of the microbial groups. Results: In this study, sandy soil samples from the surroundings of natural and artificial water resources of two distinct natures were used. Based on 16S rRNA sequencing, a total of 24,563 OTUs were detected. The metagenomic information was then categorized into 446 orders, 1036 families, 4102 genera, 213 classes, and 181 phyla. Moreover, the phylum Pseudomonadota was the most dominant microbial community across all samples, representing an average relative abundance of 34%. In addition, Actinomycetes was the most abundant class (26%). The analysis of clustered proteins assigned to COG categories provides a detailed understanding of the functional capabilities and adaptation of microbial communities in soil samples. Amino acid metabolism and transport were the most abundant categories in the soil environment. Conclusions: Metagenome analysis of sandy soils surrounding natural lakes and artificial water points in the Tubaiq conservation area of KSRNR (Saudi Arabia) has unveils rich microbial activity, highlighting the complex interactions and ecological roles of microbial communities in these environments. [ABSTRACT FROM AUTHOR]

Brassica napus is an important oil crop in China and has a great demand for nitrogen nutrients. Cationic amino acid transporters (CAT) play a key role in amino acid absorption and transport in plants. However, the CATs family has not been reported in B. napus so far. In this study, genome-wide analysis identified 22 CAT members in the B. napus genome. Based on phylogenetic and synteny analysis, BnaCATs were classified into four groups (Group I–Group IV). The members in the same subgroups showed similar physiochemical characteristics and intron/exon and motif patterns. By evaluating cis-elements in the promoter regions, we identified some cis-elements related to hormones, stress and plant development. Darwin's evolutionary analysis indicated that BnaCATs might have experienced strong purifying selection pressure. The BnaCAT family may have undergone gene expansion; the chromosomal location of BnaCATs indicated that whole-genome replication or segmental replication may play a major driving role. Differential expression patterns of BnaCATs under nitrate limitation, phosphate shortage, potassium shortage, cadmium toxicity, ammonium excess and salt stress conditions indicated that they were responsive to different nutrient stresses. In summary, these findings provide a comprehensive survey of the BnaCAT family and lay a foundation for the further functional analysis of family members. [ABSTRACT FROM AUTHOR]

It has been shown that the jejunum represents the most important site for the nutrient's absorption in several species. However, in pigs, this information seems to be controversial and limited information are available about differences in intestinal physiology between female and castrated male pigs. The trans-epithelial electrical resistance (TEER) and the active uptake of L-glutamate (L-Glu), L-arginine (L-Arg), L-methionine (L-Met) and D-glucose (D-Glu) in the jejunum and ileum of female (n = 5) and castrated male (n = 7) pigs fed a protein-restricted grower and finisher diet (128 and 112 g of crude protein/kg dry matter) were investigated. The intestine segments were collected at slaughter and mounted in Ussing chambers. Results were further investigated by protein expression analysis of the D-Glu transporter Sodium-dependent Glucose Transporter 1 (SGLT1) and using serum creatinine, non-esterified fatty acids (NEFAs) and serum glucose concentrations measurements as indicators of muscle mass deposition and metabolic status of the animals. A linear mixed-effects regression (Lme4) model was used for data analysis. Independent of sex, the uptake of both L-Met and D-Glu was higher (p < 0.001) in the ileum than in the jejunum (2.1- and 3.6-fold increases, respectively). The L-Arg uptake was higher (p = 0.001) in females compared to castrates (1.9-fold increase). No significant differences were observed between the segments in the SGLT1 protein expression, regardless of sex. Serum measurements were also not significantly different between the female and castrates. This study suggests that the ileum has an important role in the active uptake of amino acids and D-Glu uptake and differences exist between female and castrated finishing pigs. HIGHLIGHTS: The L-Arginine uptake is higher in female compared to castrated pigs. The uptake of L-methionine and D-glucose is higher in the ileum than in the jejunum. The ileum has an important role in the active uptake of amino acids and D-glucose. [ABSTRACT FROM AUTHOR]

Abstract Background Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive. Methods Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin. Results TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-β1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35. Conclusion Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling.

Background: Directly discharging livestock and poultry slaughter blood without proper treatment can cause severe ecological damage. Exploring the use of microorganisms to break down waste blood into smaller molecules such as peptides and amino acids, as well as investigating the possibility of transforming these small molecules into water-soluble fertilizers containing amino acids, holds significant research value in the comprehensive utilization of livestock and poultry blood. Results: In this study, a single strain of Bacillus pumilus NWMCC0302, which has effectively degraded bovine blood, was isolated from abattoir blood sludge using casein agar plates and Columbia blood agar plates. The degradation test was carried out using bovine raw blood as a nitrogen source in the medium, and the results showed that the strain degraded 53.83% of bovine blood under optimal degradation conditions. The whole genome sequencing of Bacillus pumilus NWMCC0302 was conducted using the second-generation DNBSEQ platform and the third-generation PacBio platform, employing high-throughput sequencing technology. The size of the strain's entire genome was determined to be 3 868 814 bp with a G-C content of 41.63%. The total gene length accounted for 88.98% of the genome length at 3 442 341 bp and encoded 4 113 genes. The strain contained 79 tRNAs, 24 rRNAs, 7 sRNAs, and 296 repetitive sequences. The gene data obtained from sequencing were also functionally annotated using the COG, KEGG, and VFDB databases. In the COG database, 310 genes were involved in amino acid transport and metabolism, including 10 catabolic proteins related to COGs. In the KEGG database, were 201 genes involved in amino acid metabolism pathways, including 8 genes in nitrogen metabolism pathways and 2 genes in oxidative pathways. The VFDB database contains two lysostaphin genes and one serine protease-hydrolyzed ClpP gene. Conclusions: In summary, Bacillus pumilus NWMCC0302 was screened for its efficient ability to degrade bovine blood. Additionally, the genetic information of Bacillus pumilus NWMCC0302 was revealed at the genetic level, providing a feasible experimental method for applying this strain to the degradation of blood from slaughtered livestock and poultry. Moreover, it is a potential functional strain for producing amino acid-containing water-soluble fertilisers. [ABSTRACT FROM AUTHOR]

The D-enantiomers of L-amino acids are non-proteinogenic but widely present in foods. This is due to spontaneous racemization or processing, such as heating or alkali treatment, leading to substantial dietary exposure. Additional exposure to D-amino acids (D-AAs) comes from the human microbiota; D-AAs are present in bacterial surface proteoglycans, essential for bacterial competition and growth. Humans and other mammals have a complex set of genes for D-AA transport and degradation, and capacity to synthesize several D-AAs. Free D-AAs are present at low levels in human tissues and body fluids, yet they are apparently of considerable physiological and pathological importance. Amino acid transport regulates their presence and favors specific D-AAs, e.g. D-serine, D-aspartate, D-cysteine, and D-glutamate, over many others. Some of these D-AAs interact with the ubiquitous glutamate-gated Ca2+ channels, affecting signaling functions in most organs, especially the intestine, kidney, and brain. Consequently, the exposures, synthesis, local and systemic transport of D-AAs could be much more biologically important in humans than previously assumed, likely playing a role in gut-organ signaling and in many degenerative diseases. [ABSTRACT FROM AUTHOR]

Introduction: For many therapeutic drugs, including antiretroviral drugs used to treat people living with HIV-1 (PLWH), we have little data on the potential effects on the developing human brain due to limited access to tissue and historical constraints on the inclusion of pregnant populations in clinical trials. Human induced pluripotent stem cells (iPSCs) offer a new avenue to gain insight on how drugs may impact human cell types representative of the developing central nervous system. To prevent vertical transmission of HIV and promote the health of pregnant PLWH, antiretroviral therapy must be initiated and/or maintained throughout pregnancy. However, many antiretroviral drugs are approved for widespread use following clinical testing only in non-pregnant populations and there may be limited information on potential teratogenicity until pregnancy outcomes are evaluated. The integrase strand transfer inhibitor dolutegravir (DTG) is a frontline antiretroviral drug that is effective in viral suppression of HIV but was previously reported to be associated with a slight increase in the risk for neural tube defects in one study, although this has not been replicated in other cohorts. Methods: To directly investigate the potential impact of DTG on human cortical neurogenesis, we measured the effects of daily drug exposure on the early stages of corticogenesis in a human iPSC-based forebrain organoid model. We quantified organoid size and structure and analyzed gene and protein expression to evaluate the impact of several doses of DTG on organoid development. Results: We observed deficits in organoid structure and impaired neurogenesis in DTG-treated organoids compared to vehicle-treated control organoids after 20 or 40 days in culture. Our highest dose of DTG (10 μM) resulted in significantly smaller organoids with a reduced density of neural rosette structures compared to vehicle-treated controls. Mechanistically, RNA-sequencing and immunohistological analysis suggests dysregulated amino acid transport and activation of the integrated stress response in the DTG-treated organoids, and functionally, a small molecule integrated stress response inhibitor (ISRIB) could partially rescue increased expression of proteins related to cell cycle regulation. Discussion: Together, these results illustrate the potential for human iPSC-based strategies to reveal biological processes during neurogenesis that may be affected by therapeutic drugs and provide complementary data in relevant human cell types to augment preclinical investigations of drug safety during pregnancy. [ABSTRACT FROM AUTHOR]

Amino acids are the main form of nitrogen in plants, and their transport across cell membranes relies on amino acid transporters (AATs). Among the plant AATs, the TaATLa subfamily comprises 18 members, yet the bioinformatics characteristics and functions of TaATLa genes in common wheat remain poorly understood due to their complex genomes. This study performed genomic analyses of TaATLas. These analyses included chromosome distributions, evolutionary relationships, collinearity, gene structures, and expression patterns. An analysis of cis-acting elements and predicted miRNA-TaATLas regulatory networks suggests that TaATLas are regulated by light, hormones, and stress signals. Functional assays revealed that TaATLa6 transports glutamine (Gln), glutamate (Glu), and aspartate (Asp) in yeast. In contrast, TaATLa4 specifically transports Gln and Asp. Furthermore, TaATLas exhibits diverse gene expression patterns, with TaATLa4-7D enhancing yeast heat tolerance in a heterologous expression system, indicating its potential role in adapting to environmental stress by regulating amino acid transport and distribution. This study sheds light on the functional roles of TaATLa genes, with implications for improving nitrogen use in wheat and other crop species. [ABSTRACT FROM AUTHOR]

Background: Streptococcus canis is a commensal bacterium in companion animals. This microorganism can infect humans who have been in deep contact with or bitten by pet dogs, suggesting that the skin/soft tissue is one of infection entry sites. To understand pathological process in human cells, we aimed to determine S. canis transcriptomic changes in invasive environments of human keratinocytes. Methods: We selected one isolate from candidates with whole-genome sequences, based on re-obtained cell invasion ability (CIA) data into human keratinocytes along with bacterial cytotoxicity. RNA-sequencing was conducted for the samples at baselines and 2 h/5 hr post-inoculation using NovaSeq 6000. Global/differential gene expression analyses [principal component analysis (PCA)/k-means clustering analysis/differentially expressed gene (DEG) analyses] were performed. We classified DEGs into their functional categories. To validate transcriptomic results, we did quantitative reverse transcription-polymerase chain reaction (qRT-PCR) assays. Results: FU1 isolate was selected from seven candidates, based on re-obtained CIA data with less cytotoxicity. Total read bases of 6.17–9.02 Gbp were obtained by RNA-sequencing. PCA and k-means clustering analysis indicated clustering according to their inoculation times. Volcano plots and Venn diagrams revealed that S. canis invasion into keratinocytes produced altered distributions of many genes. Gene ontology enrichment analysis showed most of the gene expressions were downregulated. DEG functional analysis showed the downregulated DEGs belonging to energy production and conversion/carbohydrate transport and metabolism/amino acid transport and metabolism/nucleotide transport and metabolism, with the upregulated DEGs belonging to transcription. qRT-PCR assays for downregulated/upregulated expressions of four genes (pgk–slo/opuAA–kdpB) validated transcriptomic results. Conclusion: Our observations suggest that S. canis can downregulate its metabolism-associated gene expressions in human keratinocyte environments. The observed gene expression changes can imply the latent infection in human cells. Further investigation is needed to elucidate the underlying mechanisms for the latent infection. [ABSTRACT FROM AUTHOR]

Amino acids are important for cellular metabolism. Their uptake across the plasma membrane is mediated by transport proteins. Despite the fact that the organic anion transporting polypeptide 4C1 (OATP4C1, Uniprot: Q6ZQN7) mediates transport of l‐arginine and l‐arginine derivatives, other members of the OATP family have not been characterized as amino acid transporters. The OATP family member OATP3A1 (gene symbol SLCO3A1, Uniprot: Q9UIG8) is ubiquitously expressed in human cells and highly expressed in many cancer tissues and cell lines. However, only a few substrates are known for OATP3A1. Accordingly, knowledge about its biological relevance is restricted. Our aim was to identify new substrates of OATP3A1 to gain insights into its (patho‐)physiological function. In an LC‐MS‐based untargeted metabolomics assay using untreated OATP3A1‐overexpressing HEK293 cells and control cells, we identified several amino acids as potential substrates of OATP3A1. Subsequent uptake experiments using exogenously added substrates revealed OATP3A1‐mediated transport of l‐tryptophan, l‐tyrosine, and l‐phenylalanine with 194.8 ± 28.7% (P < 0.05), 226.2 ± 18.7% (P < 0.001), and 235.2 ± 13.5% (P < 0.001), respectively, in OATP3A1‐overexpressing cells compared to control cells. Furthermore, kinetic transport parameters (Km values) were determined (Trp = 61.5 ± 14.2 μm, Tyr = 220.8 ± 54.5 μm, Phe = 234.7 ± 20.6 μm). In summary, we identified the amino acids l‐tryptophan, l‐tyrosine, and l‐phenylalanine as new substrates of OATP3A1. These findings could be used for a better understanding of (patho‐)physiological processes involving increased demand of amino acids, where OATP3A1 should be considered as an important uptake transporter of l‐tryptophan, l‐tyrosine, and l‐phenylalanine. [ABSTRACT FROM AUTHOR]

Purpose: To explore the feasibility of imaging amino-acid transport and PSMA molecular pathways in the detection of metastatic breast invasive lobular carcinoma (ILC) and if there is superior detection compared to standard-of-care imaging [computed tomography (CT)/bone scan, or 18F-FDG positron-emission-tomography (PET)-CT]. Methods: 20 women with de-novo or suspected metastatic ILC underwent two PET-CT scans with 18F-fluciclovine and 68Ga-PSMA-11 on separate days. Uptake per patient and in 3 regions per patient - ipsilateral axillary lymph node (LN), extra-axillary LN (ipsilateral supraclavicular or internal mammary), or distant sites of disease - was compared to standard-of-care imaging (CT/bone scan in 13 patients and 18F-FDG PET-CT in 7 patients). Results were correlated to a composite standard of truth. Confirmed detection rate (cDR) was compared using McNemar's test. Mean SUVmax of 18F-fluciclovine and 68Ga-PSMA-11 in the most avid lesion for each true positive metastatic region and intact primary lesion were compared by t-test. Results: The cDR for standard-of-care imaging was 5/20 patients in 5/60 regions. 68Ga-PSMA-11 PET-CT detected metastasis in 7/20 patients in 7/60 regions. 18F-fluciclovine PET-CT detected metastasis in 9/20 patients in 12/60 regions. The cDR for 18F-fluciclovine PET-CT was significantly higher versus standard-of-care imaging on the patient and combined region levels, while there were no significant differences between 68Ga-PSMA-11 and standard-of care imaging. 18F-fluciclovine cDR was also significantly higher than 68Ga-PSMA-11 on the combined region level. Mean SUVmax for true positive metastatic and primary lesions with 18F-fluciclovine (n = 18) was significantly greater than for 68Ga-PSMA-11 (n = 11) [5.5 ± 1.8 versus 3.5 ± 2.7 respectively, p = 0.021]. Conclusion: In this exploratory trial, 18F-fluciclovine PET-CT has a significantly higher cDR for ILC metastases compared to standard-of-care imaging and to 68Ga-PSMA-11. Mean SUVmax for true positive malignancy was significantly higher with 18F-fluciclovine than for 68Ga-PSMA-11. Exploratory data from this trial suggests that molecular imaging of amino acid metabolism in patients with ILC deserves further study. Clinical trial registration: Early phase (I-II) clinical trial (NCT04750473) funded by the National Institutes of Health (R21CA256280). [ABSTRACT FROM AUTHOR]

AIM: To explore the effects of moderate-altitude exposure on intestinal flora in healthy individuals. METHODS: The aid-Tibet cadres, who were sent to work from Guangdong（ average altitude < 50 m） to Nyingchi（ average altitude of 2 900 m）, were recruited. A total of 76 samples were collected, including 42 samples from healthy adults with plateau living for 0 day and 34 samples from healthy adults with plateau living for 6 months. Fecal samples DNA were extracted, sequenced by the 16S rDNA high-throughput sequencing technology and analyzed bioinformatically. RESULTS: Compared with the base group, α diversity was increased （P=4. 00×10-4） and β diversity was decreased （P=1. 00×10-3）. After moderate altitude exposure, the relative abundance of phylum Proteobacteria （|LDA|>4, P<0. 05）, genus Escherichia-Shigella, species Enterococcus_faecalis, Haemophilus_influenzae and Helicobacter_sp. _UNSW1. 7sp decreased（ adjusted P<0. 05）, wheras the relative abundance of phylum Bacteroidetes （|LDA|>4, P<0. 05）, genusButyricimona, species Lactobacillus_sp. _RA2113 （s） and Butyricimonas_sp. _Marseille-P2440 （s） increased （adjusted P<0. 05）. The functional prediction by PICRUSt showed a decrease in the relative abundance of pathway related to xenobiotics biodegradation and metabolism, membrane transport and amino acid metabolism （adjusted P<0. 05）. Conversely, the relative abundance of pathway related to biosynthesis of other secondary metabolites and nucleotide metabolism was increased （adjusted P< 0. 05）. Finally, the results of microbiome phenotype prediction by BugBase showed that moderate altitude exposure improves the gut microbiota functions involving anaerobic oxygen tolerance and gram positive （adjusted P<0. 05）. And bacteria containing facultatively anaerobic oxygen tolerance, oxidative stress tolerance, gram negative and biofilm formation in the six-group decreased significantly compared with those in base group （adjusted P<0. 05）. CONCLUSION: Moderate altitude exposure impacts the diversity, abundance and function of intestinal flora in healthy population, suggesting that altitude factors may have some influence on gut microbiota. [ABSTRACT FROM AUTHOR]

This study investigated the effects of negative energy balance (NEB) on perinatal ewes, with a focus on changes in growth performance, serum biochemical parameters, rumen fermentation, ruminal bacteria composition, placental phenotype‐related indicators, and expression levels of genes related to placental function. Twenty ewes at 130 days of gestation were randomly allocated to either the positive energy balance (PEB) or NEB groups. In the experiment, ewes in the PEB group were fed the same amount as their intake during the pre‐feeding baseline period, while ewes in the NEB group were restricted to 70% of their individual baseline feed intake. The experiment was conducted until 42 days postpartum, and five double‐lamb ewes per group were selected for slaughter. The results demonstrated that NEB led to a significant decrease in body weight, carcass weight, and the birth and weaning weights of lambs (P < 0.05). Additionally, NEB caused alterations in serum biochemical parameters, such as increased non‐esterified fatty acids and β‐hydroxybutyrate levels and decreased cholesterol and albumin levels (P < 0.05). Rumen fermentation and epithelial parameters were also affected, with a reduction in the concentrations of acetic acid, butyric acid, total acid and a decrease in the length of the rumen papilla (P < 0.05). Moreover, NEB induced changes in the structure and composition of ruminal bacteria, with significant differences in α‐diversity indices and rumen microbial community composition (P < 0.05). Gene expression in rumen papilla and ewe placenta was also affected, impacting genes associated with glucose and amino acid transport, proliferation, apoptosis, and angiogenesis (P < 0.05). These findings screened the key microbiota in the rumen of ewes following NEB and highlighted the critical genes associated with rumen function. Furthermore, this study revealed the impact of NEB on placental function in ewes, providing a foundation for investigating how nutrition in ewes influences reproductive performance. This research demonstrates how nutrition regulates reproductive performance by considering the combined perspectives of rumen microbiota and placental function. [ABSTRACT FROM AUTHOR]

For the first time, we used an in vitro vs. in vivo experimental design to reveal core pathways under nitrogen deficiency (ND) in an evergreen tree crop. These pathways were related to lignin biosynthesis, cell redox homeostasis, the defense response to fungus, the response to Karrikin, amino acid transmembrane transport, the extracellular region, the cellular protein catabolic process, and aspartic-type endopeptidase activity. In addition, the mitogen-activated protein kinase pathway and ATP synthase (ATP)-binding cassette transporters were significantly upregulated under nitrogen deficiency in vitro and in vivo. Most of the MAPK downstream genes were related to calcium signaling (818 genes) rather than hormone signaling (157 genes). Moreover, the hormone signaling pathway predominantly contained auxin- and abscisic acid-related genes, indicating the crucial role of these hormones in ND response. Overall, 45 transcription factors were upregulated in both experiments, 5 WRKYs, 3 NACs, 2 MYBs, 2 ERFs, HD-Zip, RLP12, bHLH25, RADIALIS-like, and others, suggesting their ND regulation is independent from the presence of a root system. Gene network reconstruction displayed that these transcription factors participate in response to fungus/chitin, suggesting that nitrogen response and pathogen response have common regulation. The upregulation of lignin biosynthesis genes, cytochrome genes, and strigalactone response genes was much more pronounced under in vitro ND as compared to in vivo ND. Several cell wall-related genes were closely associated with cytochromes, indicating their important role in flavanols biosynthesis in tea plant. These results clarify the signaling mechanisms and regulation of the response to nitrogen deficiency in evergreen tree crops. [ABSTRACT FROM AUTHOR]

Milk urea (MU) concentration is proposed as an indicator trait for breeding toward reduced nitrogen (N) emissions and leaching in dairy. We selected 20 German Holstein cows based on MU breeding values, with 10 cows each having low (LMUg) and high (HMUg) MU genetic predisposition. Using RNA-seq, we characterized these cows to unravel molecular pathways governing post-absorptive body N pools focusing on renal filtration and reabsorption of nitrogenous compounds, hepatic urea formation and mammary gland N excretion. While we observed minor adjustments in cellular energy metabolism in different tissues associated with different MU levels, no transcriptional differences in liver ammonia detoxification were detected, despite significant differences in MU between the groups. Differential expression of AQP3 and SLC38A2 in the kidney provides evidence for higher urea concentration in the collecting duct of LMU cows than HMU cows. The mammary gland exhibited the most significant differences, particularly in tricarboxylic acid (TCA) cycle genes, amino acid transport, tRNA binding, and casein synthesis. These findings suggest that selecting for lower MU could lead to altered urinary urea (UU) handling and changes in milk protein synthesis. However, given the genetic variability in N metabolism components, the long-term effectiveness of MU-based selection in reducing N emissions remains uncertain. [ABSTRACT FROM AUTHOR]

• Nitric oxide (NO) induce tolerance to cadmium stress. • Nitric oxide induces antioxidant defense system and osmolytes accumulation. • Nitric oxide alleviate cadmium stress by regulating genes related to signal transduction, carbohydrate transport and metabolism, amino acid biosynthesis and phenylpropane biosynthesis. Cadmium (Cd) is harmful to the environment, as it is a non-essential biological element. It leads to the normal dysfunction and degradation of soil quality, and is toxic to plants. Many studies reported that the application of nitric oxide (NO) can effectively reduce the toxicity of Cd in plants. However, the underlying molecular mechanism of the positive effects of exogenous NO on plant Cd tolerance has not been well documented. In the present study, comparative transcriptome analysis was performed on Kentucky bluegrass seedlings treated with Cd (Cd alone) and Cd + NO (Cd and NO simultaneously).Comparative transcriptional regulation analysis showed that Differential expressed genes (DEGs) was mainly involved in mitogen-activated protein kinase (MAPK) signal transduction, plant hormone signal transduction, phenylpropanoid biosynthesis, amino acid transport and metabolism, fatty acid metabolism and biosynthesis related pathways. These results suggest that exogenous NO may alleviate cadmium stress by regulating genes related to signal transduction, carbohydrate transport and metabolism, amino acid biosynthesis and phenylpropane biosynthesis. Additionally, the DEGs and metabolic pathways between Cd and Cd + NO treatment groups were analyzed in this study, and a series of key genes mediated by NO signal in response to cadmium stress were screened out, and they were listed as candidate genes related to NO alleviating cadmium stress in Kentucky bluegrass. This study helps to understand the transcriptional regulation and complex internal network of exogenous NO alleviating Cd -tolerance in Kentucky bluegrass. [ABSTRACT FROM AUTHOR]

Solute carrier (SLC) 38 family, responsible for transmembrane transport of neutral amino acids, plays a role in the proliferation, invasion, and metastasis of cancer cells, but its role in gastric cancer (GC) progression remains unclear. This study aimed to explore the biological effects of SLC38A7 and its regulatory mechanisms in GC. RNA expression data, tumor tissue specimens, and GC cell lines were used for bioinformatics and experimental analyses. Cell Counting Kit-8 assay, wound healing assay, and Transwell invasion assay were used to evaluate cell viability, migration, and invasion, respectively. Oxidative phosphorylation, mitochondrial membrane potential, and expression of the critical proteins in the mitochondrial respiratory chain were assayed using extracellular flux analysis, flow cytometry, and Western blot, respectively. RNA immunoprecipitation assay was used to explore the mechanisms of N6-methyladenosine (m6A) methylation. SLC38A7 was upregulated in GC tissue and cell lines. SLC38A7 silencing suppressed cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in cancer cells. SLC38A7 overexpression had the opposite biological effects. Interactions between SLC38A7 and methyltransferase like 3 (METTL3) or insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) were detected. SLC38A7 mRNA stability was maintained by METTL3--IGF2BP2 axis in an m6A-dependent manner. Our results suggest that SLC38A7, stabilized by METTL3 and IGF2BP2-mediated m6A methylation, enhances cell viability, migration, invasion, oxidative phosphorylation, and mitochondrial function in GC, highlighting its role as a potential therapeutic target for GC. [ABSTRACT FROM AUTHOR]

The article in the Journal of Plant Pathology discusses the complete genome sequence of the endophytic Bacillus subtilis GUCC4, a potential biocontrol agent for managing Nigrospora pathogens that cause leaf blight disease in passion fruit. The study highlights the strain's inhibitory effects on N. sphaerica, its biocontrol determinants such as amylase and protease, and its capacity to synthesize secondary metabolites with antifungal properties. The genome annotation reveals 4,446 protein-coding genes and 14 secondary metabolite biosynthetic gene clusters, emphasizing GUCC4's potential as an eco-friendly alternative to synthetic fungicides for plant disease management. [Extracted from the article]

Introduction: Low temperature inhibits the growth of most microorganisms. However, some microbes can grow well in a low temperature, even a freezing temperature. Methods: In this study, the mechanisms conferring cold resistance in the cryophylactic yeast Metschnikowia (M.) pulcherrima MS612, an isolate of the epidermis of ice grapes, were investigated based on comparative transcriptome analysis. Results: A total of 6018 genes and 374 differentially expressed genes (> 2-fold, p < 0.05) were identified using RNA-Seq. The differentially expressed genes were mainly involved in carbohydrate and energy metabolism, transport mechanisms, antifreeze protection, lipid synthesis, and signal transduction. M. pulcherrima MS612 maintained normal growth at low temperature (5°C) by enhancing energy metabolism, sterol synthesis, metal ion homeostasis, amino acid and MDR transport, while increased synthesis of glycerol and proline transport to improve its resistance to the freezing temperature (-5°C). Furthermore, cAMPPKA and ERAD signaling pathways contribute to resist the low temperature and the freezing temperature, respectively. Conclusion: This study provides new insights into cold resistance in cryophylactic microorganisms for maneuvering various metabolism to resist different cold environment. [ABSTRACT FROM AUTHOR]

ABSTRACT Priority effects, where the order and timing of species arrival influence the assembly of ecological communities, have been observed in a variety of taxa and habitats. However, the genetic and molecular basis of priority effects remains unclear, hindering a better understanding of when priority effects will be strong. We sought to gain such an understanding for the nectar yeast Metschnikowia reukaufii commonly found in the nectar of our study plant, the hummingbird‐pollinated Diplacus (Mimulus) aurantiacus. In this plant, M. reukaufii can experience strong priority effects when it reaches flowers after other nectar yeasts, such as M. rancensis. After inoculation into two contrasting types of synthetic nectar simulating early arrival of M. rancensis, we conducted whole‐transcriptome sequencing of 108 strains of M. reukaufii. We found that several genes were differentially expressed in M. reukaufii strains when the nectar had been conditioned by growth of M. rancensis. Many of these genes were associated with amino acid metabolism, suggesting that M. reukaufii strains responded molecularly to the reduction in amino acid availability caused by M. rancensis. Furthermore, investigation of expression quantitative trait loci (eQTLs) revealed that genes involved in amino acid transport and resistance to antifungal compounds were enriched in some genetic variants of M. reukaufii. We also found that gene expression was associated with population growth rate, particularly when amino acids were limited. These results suggest that intraspecific genetic variation in the ability of nectar yeasts to respond to nutrient limitation and direct fungal competition underpins priority effects in this microbial system. [ABSTRACT FROM AUTHOR]

During ovulation, the apical wall of the preovulatory follicle breaks down to facilitate gamete release. In parallel, the residual follicle wall differentiates into a progesterone-producing corpus luteum. Disruption of ovulation, whether through contraceptive intervention or infertility, has implications for women's health. In this study, we harness the power of an ex vivo ovulation model and machine-learning guided microdissection to identify differences between the ruptured and unruptured sides of the follicle wall. We demonstrate that the unruptured side exhibits clear markers of luteinization after ovulation while the ruptured side exhibits cell death signals. RNA-sequencing of individual follicle sides reveals 2099 differentially expressed genes (DEGs) between follicle sides without ovulation induction, and 1673 DEGs 12 h after induction of ovulation. Our model validates molecular patterns consistent with known ovulation biology even though this process occurs in the absence of the ovarian stroma, vasculature, and immune cells. We further identify previously unappreciated pathways including amino acid transport and Jag-Notch signaling on the ruptured side and glycolysis, metal ion processing, and IL-11 signaling on the unruptured side of the follicle. This study yields key insights into follicle-inherent, spatially-defined pathways that underlie follicle rupture, which may further understanding of ovulation physiology and advance women's health. Molecular profiling of ex vivo ovarian follicles reveals key asymmetric pathways that underlie follicle rupture and luteinization during ovulation [ABSTRACT FROM AUTHOR]

Spinal cord injury (SCI) is a debilitating central nervous system (CNS) disorder that leads to significant motor and sensory impairments. Given the limited regenerative capacity of adult mammalian neurons, this study presents an innovative strategy to enhance axonal regeneration and functional recovery by identifying a novel factor that markedly promotes axonal regeneration. Employing a zebrafish model with targeted single axon injury in Mauthner cells (M-cells) and utilizing the Tg (Tol056: EGFP) transgenic line for in vivo monitoring, we investigate the intrinsic mechanisms underlying axonal regeneration. This research specifically examines the role of amino acid transport, emphasizing the role of the solute carrier 1A4 amino acid transporter in axonal regeneration. Our findings demonstrate that Slc1a4 overexpression significantly enhances axonal regeneration in M-cells, whereas Slc1a4 deficiency impedes this process, which is concomitant with the downregulation of the P53/Gap43 signaling pathway. By elucidating the fundamental role of Slc1a4 in axonal regeneration and uncovering its underlying mechanisms, this study thus provides novel insights into therapeutic strategies for SCI. [ABSTRACT FROM AUTHOR]

Maternal hyperhomocysteinemia (HHcy) is a risk factor for intrauterine growth restriction presumably caused by a decrease in the placental transport of nutrients. We investigated the effect of experimental HHcy induced by daily methionine administration to pregnant rats on the free amino acid levels in the maternal and fetal blood, as well as on morphological and biochemical parameters associated with the amino acid transport through the placenta. HHcy caused an increase in the levels of most free amino acids in the maternal blood on gestational day 20, while the levels of some amino acids in the fetal blood were decreased. In rats with HHcy, the maternal sinusoids in the placental labyrinth were narrowed, which was accompanied by aggregation of red blood cells. We also observed an increase in the neutral amino acid transporters (LAT1, SNAT2) protein levels and activation of 4E-BP1, a downstream effector of mTORC1 complex, in the labyrinth zone. Maternal HHcy affected the placental barrier permeability, as evidenced by intensification of the mother-to-fetus transfer of Evans Blue dye. The imbalance in the free amino acid levels in the maternal and fetal blood in HHcy may be due to the competition of homocysteine with other amino acids for common transporters, as well as a decrease in the area of exchange zone between maternal and fetal circulations in the placental labyrinth. Upregulation of the neutral amino acid transporter expression in the labyrinth zone may be a compensatory response to an insufficient intrauterine amino acid supply and fetal growth restriction. [ABSTRACT FROM AUTHOR]

Background: Aflatoxin B1 (AFB1) is a prevalent contaminant in agricultural products, presenting significant risks to animal health. CotA laccase from Bacillus licheniformis has shown significant efficacy in degrading mycotoxins in vitro test. The efficacy of Bacillus CotA laccase in animals, however, remains to be confirmed. A 2 × 2 factorial design was used to investigate the effects of Bacillus CotA laccase level (0 or 1 U/kg), AFB1 challenge (challenged or unchallenged) and their interactions on ducks. The purpose of this study was to evaluate the efficacy of Bacillus CotA laccase in alleviating AFB1 toxicosis of ducks. Results: Bacillus CotA laccase alleviated AFB1-induced declines in growth performance of ducks accompanied by improved average daily gain (ADG) and lower feed/gain ratio (F/G). Bacillus CotA laccase ameliorated AFB1-induced gut barrier dysfunctions and inflammation testified by increasing the jejunal villi height/crypt depth ratio (VH/CD) and the mRNA expression of tight junction protein 1 (TJP1) and zonula occluden-1 (ZO-1) as well as decreasing the expression of inflammation-related genes in the jejunum of ducks. Amino acid metabolome showed that Bacillus CotA laccase ameliorated AFB1-induced amino acid metabolism disorders evidenced by increasing the level of glutamic acid in serum and upregulating the expression of amino acid transport related genes in jejunum of ducks. Bacillus CotA laccase ameliorated AFB1-induced liver injury testified by suppressing oxidative stress, inhibiting apoptosis, and downregulating the expression of hepatic metabolic enzyme related genes of ducks. Moreover, Bacillus CotA laccase degraded AFB1 in digestive tract of ducks, resulting in the reduced absorption level of AFB1 across intestinal epithelium testified by the decreased level of AFB1-DNA adduct in the liver, and the reduced content of AFB1 residues in liver and feces of ducks. Conclusions: Bacillus CotA laccase effectively improved the growth performance, intestinal health, amino acid metabolism and hepatic aflatoxin metabolism of ducks fed AFB1 diets, highlighting its potential as an efficient and safe feed enzyme for AFB1 degradation in animal production. [ABSTRACT FROM AUTHOR]

Increased plasma concentrations of glucagon (hyperglucagonemia) are reported in patients with type 2 diabetes (T2D) and are considered a diabetogenic risk factor. Emerging evidence suggests that hepatic steatosis in obesity is causing a condition of resistance toward glucagon's effects on amino acid metabolism, resulting in an amino acid-induced hyperglucagonemia. We investigated the presence of hyperglucagonemia in individuals with biopsy-verified metabolic dysfunction-associated steatotic liver disease (MASLD), and whether body mass index (BMI), T2D, hepatic steatosis, and/or fibrosis contribute to this relationship. To dissect potential mechanisms, we also determined hepatic gene expression related to amino acid transport and catabolism. Individuals with MASLD had hyperglucagonemia {controls (n = 74) vs. MASLD (n = 106); median [Q1, Q3]; 4 [3, 7] vs. 8 [6, 13] pM), P < 0.0001} and were glucagon resistant (assessed by the glucagon-alanine index) {1.3 [0.9, 2.1] vs. 3.3 [2.1, 5.3] pM·mM, P < 0.0001}. These changes were associated with hepatic steatosis (P < 0.001, R2 > 0.25) independently of BMI, sex, age, and T2D. Plasma levels of glucagon were similar in individuals with MASLD when stratified on T2D status {MASLD-T2D (n = 52) vs. MASLD + T2D (n = 54); 8 [6, 11] vs. 8 [6, 13] pM, P = 0.34} and hepatic fibrosis {MASLD + F0 (n = 25) vs. MASLD + F1-F3 (n = 67); 8.4 [7.0, 13.3] vs. 7.9 [5.2, 11.6] pM, P = 0.43}. Obesity (BMI = 30 kg/m2) did not alter glucagon levels (P = 0.65) within groups (control/MASLD). The mRNA expression of proteins involved in amino acid transport and catabolism was downregulated in MASLD. Thus, relative hyperglucagonemia is present in individuals with biopsy-verified MASLD, and hepatic steatosis partially drives hyperglucagonemia and glucagon resistance, irrespective of T2D, BMI, and hepatic fibrosis. NEW & NOTEWORTHY: Individuals with metabolic dysfunction-associated steatotic liver disease (MASLD) present with increased plasma levels of glucagon (hyperglucagonemia), irrespective of body mass index (BMI) and type 2 diabetes. Therefore, MASLD and the resultant hyperglucagonemia may act as a diabetogenic risk factor. Notably, hepatic steatosis was a significant contributor to the hyperglucagonemia in MASLD, potentially unveiling a pathway for the hyperglucagonemia in some patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

Acinetobacter is an important opportunistic pathogen associated with severe infections in humans and animals worldwide. In veterinary medicine, the resistance patterns of Acinetobacter species remain unclear, with limited information available. This study examined the genomics characterization and antimicrobial resistance of Acinetobacter strains from swine industry of Shanxi province in China. The analysis of core genome phylogenetic and antibiotic genetic determinants from Acinetobacter has shown that the number of specific core genes varied from 105 to 293, with TG9 as an outlier. Functional gene annotation from COG, GO, and KEGG analyses revealed high consistency, particularly in genes related to amino acid transport, metabolism, transcription, and energy production. Meanwhile, these strains exhibited the endemic characteristics of Acinetobacter spp., as well as the close evolutionary relationships of antibiotic resistance genes. All isolated strains had a high multidrug resistance (50%), which highlights their pathogenic for oxacillin (79.2%), cefazolin (41.7%), cotrimoxazole (50%), and tetracycline (25%). Upon treatment with ampicillin, cefotaxime, and sulfonamides, the expression of OXA51, AmpC, abeM, abeS, TEM, and sul2 mRNA in various specific Acinetobacter strains were elevated to different extents, particularly pronounced upregulation in A. baumannii. This study significantly advances our understanding of antibiotic resistance in foodborne Acinetobacter. It provides valuable theoretical insights for controlling the spread of Acinetobacter species and reducing the associated public health risks. [ABSTRACT FROM AUTHOR]

Our previous studies have found that functional changes in the hippocampal circuit from dentate gyrus (DG) to cornu ammonis 3 and 1 (CA3, CA1) are highly associated with schizophrenia (SZ). However, no studies have explored the genetic expression across the three and two human hippocampal subfields (DG-CA3-CA1 and CA3-CA1) between subjects with SZ and healthy controls (CT). We matched cohorts between CT (n = 13) and SZ (n = 13). Among SZ, 6 subjects were on antipsychotics (AP) while 7 were off AP. We combined RNA-seq data from all three and two hippocampal subfields and performed differentially expressed gene analyses across DG-CA3-CA1 and CA3-CA1 affected by either SZ or AP. We found that differentially expressed genes (DEGs) from effects of SZ and AP across DG-CA3-CA1 and CA3-CA1 were highly associated with gene ontology terms related to hormonal and immune signaling, cellular mitosis and apoptosis, ion and amino acid transports, and protein modification and degradation. Additionally, we found that multiple genes related to solute-carrier family and immune signaling were significantly upregulated across DG-CA3-CA1 and CA3-CA1 in patients with SZ relative to CT, and AP consistently and robustly repressed the expression of these upregulated genes in the DG-CA3-CA1 and CA3-CA1 from subjects with SZ. Together, these data suggest that the upregulated solute-carrier family genes in the hippocampus might have important roles in the pathophysiology of SZ, and that AP may reduce the symptoms of psychosis in SZ via rescuing the solute-carrier gene expression. [ABSTRACT FROM AUTHOR]

Due to increasingly serious soil salinisation, exploring high‐quality closely related wild species is an effective means to solve food security problems. In this study, based on comprehensive metabolomics and transcriptomics analyses of the types, quantities, metabolic pathways and gene expression of small molecule metabolites in cotyledons and embryo axis/root, we report the strategies used by barren‐tolerant wild soybean (GS2) to resist salt stress during the post‐germination period. Our results showed that salt tolerance in GS2 cotyledons mainly involves the enhanced mobilisation of reserves, including lipid and sugar breakdown and utilisation, as well as protein breakdown and, in particular, the transport of amino acids to the embryo axis/root. Moreover, antioxidant capacity is enhanced through the promotion of ascorbic acid and naringin synthesis. We also found that under salt stress, the GS2 embryo axis/root accumulates proline by promoting the ornithine biosynthetic pathway, while stimulating glutathione metabolism to eliminate excess reactive oxygen species and restore oxidative balance. In addition, to establish and elongate the embryo axis/root, lignin synthesis is enhanced by the promotion of the shikimic acid pathway, which compensates for the decrease in cell wall support caused by salt stress. This study lays the foundation for developing and utilising high‐quality wild plant resources. [ABSTRACT FROM AUTHOR]

A patient-tailored therapy of the heterogeneous, neuropsychiatric disorder of Parkinson's disease (PD) aims to improve dopamine sensitive motor symptoms and associated non-motor features. A repeated, individual adaptation of dopamine substituting compounds is required throughout the disease course due to the progress of neurodegeneration. Therapeutic drug monitoring of dopamine substituting drugs may be an essential tool to optimize drug applications. We suggest plasma determination of levodopa as an initial step. The complex pharmacology of levodopa is influenced by its short elimination half-life and the gastric emptying velocity. Both considerably contribute to the observed variability of plasma concentrations of levodopa and its metabolite 3-O-methyldopa. These amino acids compete with other aromatic amino acids as well as branched chain amino acids on the limited transport capacity in the gastrointestinal tract and the blood brain barrier. However, not much is known about plasma concentrations of levodopa and other drugs/drug combinations in PD. Some examples may illustrate this lack of knowledge: Levodopa measurements may allow further insights in the phenomenon of inappropriate levodopa response. They may result from missing compliance, interactions e.g. with treatments for other mainly age-related disorders, like hypertension, diabetes, hyperlipidaemia, rheumatism or by patients themselves independently taken herbal medicines. Indeed, uncontrolled combination of compounds for accompanying disorders as given above with PD drugs might increase the risk of side effects. Determination of other drugs used to treat PD in plasma such as dopamine receptor agonists, amantadine and inhibitors of catechol-O-methyltransferase or monoamine oxidase B may refine and improve the value of calculations of levodopa equivalents. How COMT-Is change levodopa plasma concentrations? How other dopaminergic and non-dopaminergic drugs influence levodopa levels? Also, delivery of drugs as well as single and repeated dosing and continuous levodopa administrations with a possible accumulation of levodopa, pharmacokinetic behaviour of generic and branded compounds appear to have a marked influence on efficacy of drug treatment and side effect profile. Their increase over time may reflect progression of PD to a certain degree. Therapeutic drug monitoring in PD is considered to improve the therapeutic efficacy in the course of this devastating neurologic disorder and therefore is able to contribute to the patients' precision medicine. State-of-the-art clinical studies are urgently needed to demonstrate the usefulness of TDM for optimizing the treatment of PD. [ABSTRACT FROM AUTHOR]

Exogenous brassinolide (BR) and strigolactones (SLs) play an important role in alleviating salt stress in maize. We studied the morphological and physiological responses of the salt-sensitive genotype PH4CV and salt-tolerant genotype Zheng58 to BR (1.65 nM), SL (1 µM), and BS (1.65 nM BR + 1 µM SL) under salt stress. Phenotypic analysis showed that salt stress significantly inhibited the growth of maize seedlings and significantly increased the content of Na+ in the roots. Exogenous hormones increased oxidase activity and decreased Na+ content in the roots and mitigated salt stress. Transcriptome analysis showed that the interaction of BR and SL is involved in photosynthesis–antenna proteins, the TCA cycle, and plant hormone signal transduction pathways. This interaction influences the expression of chlorophyll a/b-binding protein and glucose-6-phosphate isomerase 1 chloroplastic, and aconitase genes are affected. Furthermore, the application of exogenous hormones regulates the expression of genes associated with the signaling pathways of cytokinin (CK), gibberellins (GA), auxin (IAA), brassinosteroid (BR), abscisic acid (ABA), and jasmonic acid (JA). Additionally, exogenous hormones inhibit the expression of the AKT2/3 genes, which are responsible for regulating ion transduction and potassium ion influx. Four candidate genes that may regulate the seedling length of maize were screened out through WGCNA. Respective KOG notes concerned inorganic ion transport and metabolism, signal transduction mechanisms, energy production and conversion, and amino acid transport and metabolism. The findings of this study provide a foundation for the proposition that BR and SL can be employed to regulate salt stress alleviation in maize. [ABSTRACT FROM AUTHOR]

Microsporidia are unfriendly microorganisms, and their infections cause considerable damage to economically or environmentally important insects like silkworms and honeybees. Thus, the identification of measures to improve host resistance to microsporidia infections is critically needed. Here, an overexpressed miR-6498-5p transgenic silkworm line was constructed. Importantly, the survival rates and median lethal doses of the transgenic line were clearly higher after infection with Nosema bombycis. H&E staining and RT-qPCR analyses revealed an inhibitory effect on the proliferation of N. bombycis in the transgenic larvae. Metabolomics analysis further revealed the presence of 56 differential metabolites between the two lines. KEGG analysis of these 56 metabolites found that they were involved in various amino acid and vitamin metabolism pathways. Notably, VB6 metabolism was enriched among the metabolites, and the pathway was well known for its involvement in the synthesis, interconversion, and degradation of amino acids. These suggest that miR-6498-5p modifies parasitic environments to inhibit the proliferation of N. bombycis by affect ing the host amino acid metabolism. These results demonstrate the potential of microRNAs as biomolecules that can promote resistance to microsporidia and provide new insights and a new approach to generate microsporidia-resistant biological materials. IMPORTANCE Microsporidia have an extremely wide host range and are capable of infecting a wide variety of insects and vertebrates, including humans, and their lethality to multiple species often poses significant environmental management challenge. Here, we successfully constructed a microsporidium-resistant line in the silkworm, based on the overexpression of miR-6498-5p. Our results strongly support the hypothesis that miR-6498-5p efficiently suppresses the proliferation of Nosema bombycis by regulating the host VB6 metabolism, a key pathway for enzymes involved in amino acid transport and protein metabolism. Our study provides new insights for understanding host anti-pathogen defenses toward microsporidia. [ABSTRACT FROM AUTHOR]

Amino acid transporters play a vital role in cellular homeostasis by maintaining protein synthesis. L-type amino acid transporter 1 (LAT1/SLC7A5/CD98lc) is a major transporter of large neutral amino acids in cancer cells because of its predominant expression. Although amino acid restriction with various amino acid analog treatments is known to induce mitotic defects, the involvement of amino acid transporters in cell division remains unclear. In this study, we identified that LAT1 is responsible for mitotic progression in a transport activity-independent manner. LAT1 knockdown activates the spindle assembly checkpoint, leading to a delay in metaphase. LAT1 maintains proper spindle orientation with confinement of the lateral cortex localization of the NuMA protein, which mediates the pulling force against the mitotic spindle toward the lateral cortex. Unexpectedly, JPH203, an inhibitor of LAT1 amino acid transport activity, does not affect mitotic progression. Moreover, the transport activity-deficient LAT1 mutant maintains the proper spindle orientation and mitotic progression. LAT1 forms a heterodimer with CD98 (SLC3A2/CD98hc) both in interphase and mitosis. Although CD98 knockdown decreases the plasma membrane localization of LAT1, it does not affect mitotic progression. LAT1 is localized to the Golgi and ER not only at the plasma membrane in interphase, and promotes Golgi unlinking during the mitotic entry, leading to centrosome maturation. These results suggest that LAT1 supports mitotic progression in an amino acid transport activity-independent manner and that Golgi-localized LAT1 is important for mitotic progression through the acceleration of Golgi unlinking and centrosome maturation. These findings reveal a novel LAT1 function in mitosis. [ABSTRACT FROM AUTHOR]

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Background: Cardiac maladaptive remodeling is one of the leading causes of heart failure with highly complicated pathogeneses. The E3 ligase tripartite motif containing 35 (TRIM35) has been identified as a crucial regulator governing cellular growth, immune responses, and metabolism. Nonetheless, the role of TRIM35 in fibroblasts in cardiac remodeling remains elusive. Methods: Heart tissues from human donors were used to verify tissue-specific expression of TRIM35. Fibroblast-specific Trim35 gene knockout mice (Trim35cKO) were used to investigate the function of TRIM35 in fibroblasts. Cardiac function, morphology, and molecular changes in the heart tissues were analyzed after transverse aortic constriction (TAC) surgery. The mechanisms by which TRIM35 regulates fibroblast phenotypes were elucidated using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and RNA sequencing (RNA-Seq). These findings were further validated through the use of adenoviral and adeno-associated viral transfection systems, as well as the mTORC1 inhibitor Rapamycin. Results: TRIM35 expression is primarily up-regulated in cardiac fibroblasts in both murine and human fibrotic hearts, and responds to TGF-β1 stimulation. Specific deletion of TRIM35 in cardiac fibroblasts significantly improves cardiac fibrosis and hypertrophy. Consistently, the overexpression of TRIM35 promotes fibroblast proliferation, migration, and differentiation. Through paracrine signaling, it induces hypertrophic growth of cardiomyocytes. Mechanistically, we found that TRIM35 interacts with, ubiquitinates, and up-regulates the amino acid transporter SLC7A5, which enhances amino acid transport and activates the mTORC1 signaling pathway. Furthermore, overexpression of SLC7A5 significantly reverses the reduced cardiac fibrosis and hypertrophy caused by conditional knockout of TRIM35. Conclusion: Our findings demonstrate a novel role of fibroblast-TRIM35 in cardiac remodeling and uncover the mechanism underlying SLC7A5-mediated amino acid transport and mTORC1 activation. These results provide a potential novel therapeutic target for treating cardiac remodeling. [ABSTRACT FROM AUTHOR]

Various species of rhizobium establish compatible symbiotic relationships with soybean (Glycinemax) leading to the formation of nitrogen-fixing nodules in roots. The formation of functional nodules is mediated through complex developmental and transcriptional reprogramming that involves the activity of thousands of plant genes. However, host transcriptome that differentiate between functional or nonfunctional nodules remain largely unexplored. In this study, we investigated differential compatibilities between rhizobium strains (Bradyrhizobium diazoefficiens USDA110 Bradyrhizobium sp. strain LVM105) and cultivated and wild soybeans. The nodulation assays revealed that both USDA110 and LVM105 strains effectively nodulate G. soja but only USDA110 can form symbiotic relationships with Williams 82. LVM105 formed pseudonodules on Williams 82 that consist of a central nodule-like mass that are devoid of any rhizobia. RNA-seq data revealed that USDA110 and LVM105 induce distinct transcriptome programing in functional mature nodules formed on G. soja roots, where genes involved in nucleosome assembly, DNA replication, regulation of cell cycle, and defense responses play key roles. Transcriptome comparison also suggested that activation of genes associated with cell wall biogenesis and organization and defense responses together with downregulation of genes involved in the biosynthesis of isoprenoids and antioxidant stress are associated with the formation of non-functional nodules on Williams 82 roots. Moreover, our analysis implies that increased activity of genes involved in oxygen binding, amino acid transport, and nitrate transport differentiates between fully-developed nodules in cultivated versus wild soybeans. [ABSTRACT FROM AUTHOR]

Objective • The purpose of this study is to gain a better understanding of the impact of microgravity on antibiotic resistance. Methods • K. pneumoniae original (KPO) strain was cultured under either simulated microgravity (SMG) conditions with background antibiotic exposure (SMGA) for the experimental strain or a normal gravity condition with background antibiotic exposure (NGA) for the control strain. The K. pneumoniae original (KPO) strain was also cultured under normal gravity (NG) as an additional control. Antibiotic susceptibility was evaluated prior to their incubation under SMGA, NGA, or NG conditions. After 20 cycles of incubation, antibiotic susceptibility, genomic, transcriptomic, and proteomic tests were conducted on them. Results • SMGA and NGA strains both showed resistance to ciprofloxacin and intermediate resistance to levofloxacin. Genes associated with antibiotic resistance of Klebsiella pneumoniae, including acrB, oqxB, oqxA, ompC, ompF, and tolC were found to be differently expressed between SMGA and NGA strains or between SMGA and NG strains. It was found that the biggest family of genes in the differently expressed gene (DEG) cluster between SMGA and NGA and between SMGA and NG was the same, paaBCDFGHI, but with opposite change direction, i.e., downregulation between SMGA and NGA strains, while upregulation between SMGA and NG strains. Besides, the top-ranking functional descriptions in terms of the number of DEGs whether between SMGA and NGA or between SMGA and NG were “amino acid transport and metabolism”, “carbohydrate transport and metabolism”, “transcription”, and “inorganic ion transport and metabolism”. Two pathways of “citrate cycle (TCA cycle)” and “oxidative phosphorylation” were significantly enriched by DEGs both between SMGA and NGA and between SMGA and NG. Conclusion • Our study confirmed that low levels of antibiotics present in SMG can select for resistant K. pneumoniae strains. However, SMG did not alter the antibiotic resistance in K. pneumoniae induced by exposure to trace antibiotic. [ABSTRACT FROM AUTHOR]