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Amino acid metabolic remodeling is a hallmark of cancer, driving an increased nutritional demand for amino acids. Amino acids are pivotal for energetic regulation, biosynthetic support, and homeostatic maintenance to stimulate cancer progression. However, the role of phenylalanine in multiple myeloma (MM) remains unknown. Here, we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow (BM) cells. After the treatment, phenylalanine levels increase in plasma and decrease in BM. This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression. The requirement for phenylalanine by MM cells exhibits a similar pattern. Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib (BTZ) treatment in vitro and murine models. Mechanistically, phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3-CHOP-DR5 pathway. Interference with ATF3 significantly affects phenylalanine deprivation therapy. In conclusion, we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling. Phenylalanine is necessary for MM proliferation, and its aberrant demand highlights the importance of low-phenylalanine diets as an adjuvant treatment for MM.

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The availability of high-frequency, real-time measurements of the concentrations of specific metabolites in cell culture systems will enable a deeper understanding of cellular metabolism and facilitate the application of good laboratory practice standards in cell culture protocols. However, currently available approaches to this end either are constrained to single-time-point and single-parameter measurements or are limited in the range of detectable analytes. Electrochemical aptamer-based (EAB) biosensors have demonstrated utility in real-time monitoring of analytes in vivo in blood and tissues. Here, we characterize a pH-sensing capability of EAB sensors that is independent of the specific target analyte of the aptamer sequence. We applied this dual-purpose EAB to the continuous measurement of pH and phenylalanine in several in vitro cell culture settings. The miniature EAB sensor that we developed exhibits rapid response times, good stability, high repeatability, and biologically relevant sensitivity. We also developed and characterized a leak-free reference electrode that mitigates the potential cytotoxic effects of silver ions released from conventional reference electrodes. Using the resulting dual-purpose sensor, we performed hourly measurements of pH and phenylalanine concentrations in the medium superfusing cultured epithelial tumor cell lines (A549, MDA-MB-23) and a human fibroblast cell line (MRC-5) for periods of up to 72 h. Our scalable technology may be multiplexed for high-throughput monitoring of pH and multiple analytes in support of the broad metabolic qualification of microphysiological systems.

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The occupancy of the binding pocket by the substrate ultimately determines the outcome of enzyme catalysis. Previous engineering and substrate scope of phenylalanine aminomutase from Taxus chinensis (TcPAM) has generated valuable knowledge about the regioselectivity with biocatalytic potentials for the preparation of α- and ß-phenylalanine and their derivatives. However, the significantly different regioselectivity during the amination of cinnamates by TcPAM is not fully understood. In this study, we take a reconstruction approach to change the whole binding pocket of TcPAM for probing the factors affecting the regioselectivity, resulting in variant C107S/Q319M/I431V reaching a 25.5-fold enhancement of the ß/α product ratio toward trans-cinnamate acid. Furthermore, when substituted cinnamates were used as substrates, the regioselectivity was strongly correlated with various changes in the binding pocket, and value-added 2-Cl-α-Phe (100% α-selectivity) and 4-CH3-ß-Phe (98% ß-selectivity) were individually verified by the mutants L104A and Q319M at a preparative scale, exemplifying the application feasibility of our engineering strategy. The present study uncovered the cooperative connection between aromatic binding and carboxylate binding to affect the regioselectivity, which provides new insights into the determinants of the regioselectivity possessed by TcPAM and paves the way for its biocatalytic applications on phenylalanine derivatives.

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The lignocellulosic feedstock of woody bamboo shows promising potential as an alternative to conventional wood, attributed to its excellent properties. The content and distribution of lignin serve as the foundation of these properties. While the regulation of lignin biosynthesis in bamboo has been extensively studied at the transcriptional level, its posttranslational control has remained poorly understood. This study provides a ubiquitinome dataset for moso bamboo (Phyllostachys edulis), identifying 13015 ubiquitinated sites in 4849 unique proteins. We further identified Kelch repeat F-boxprotein 9 (PeKFB9) that plays a negative role in lignin biosynthesis. Heterologous expression of PeKFB9 resulted in reduced accumulation of lignin and decreased phenylalanine ammonia-lyase (PAL) activities. Both in vitro and in vivo assays identified interaction between PeKFB9 and PePAL10. Further examination revealed that SCFPeKFB9 mediated the ubiquitination and degradation of PePAL10 via the 26S proteasome pathway. Moreover, PebZIP28667 could bind to the PePAL10 promoter to significantly inhibit its transcription, and ubiquitination of PebZIP28667 weakened this inhibition. Collectively, our findings reveal a PeKFB9-PePAL10/PebZIP28667-PePAL10 module that acts as a negative regulator of lignin biosynthesis. This study advances our understanding of posttranslational regulation in plant lignification, which will facilitate the improvement of the properties of bamboo wood and the breeding of varieties.

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Gut microbial metabolites have been demonstrated to play a role in diabetes mellitus and gestational diabetes mellitus (GDM). This study aimed to investigate gut microbiome, fecal metabolomics, and their association in pregnant women with and without GDM. The metabolome indicated that the top 2 differential metabolic pathways between control (Con) and GDM groups were phenylalanine metabolism and nucleotide metabolism. The increased Phenylalanylglycine, m-coumaric acid, and Phenylacetic acid were among the top differential metabolites between Con and GDM groups and involved in phenylalanine metabolism. Uracil and hypoxanthine were top differential metabolites in Con vs. GDM and involved in nucleotide metabolism. The proficiently altered gut microbiota at the class level was c_unclassified_ Firmicutes. Association analysis between gut microbiota and fecal metabolites indicated that the increased gut symbiont Clostridium belonged to Firmicutes and was linked to the dysregulation of phenylalanine metabolism in GDM. This study may provide the mechanism underlying how Clostridium-phenylalanine metabolism association contributes to GDM pathogenesis and also be a novel therapeutic strategy to treat GDM.

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BACKGROUND: Phenylalanine ammonia-lyase (PAL) serves as a key gateway enzyme, bridging primary metabolism and the phenylpropanoid pathway, and thus playing an indispensable role in flavonoid, anthocyanin and lignin biosynthesis. PAL gene families have been extensively studied across species using public genomes. However, a comprehensive exploration of PAL genes in Epimedium species, especially those involved in prenylated flavonol glycoside, anthocyanin, or lignin biosynthesis, is still lacking. Moreover, an in-depth investigation into PAL gene family evolution is warranted. RESULTS: Seven PAL genes (EpPAL1-EpPAL7) were identified. EpPAL2 and EpPAL3 exhibit low sequence identity to other EpPALs (ranging from 61.09 to 64.38%) and contain two unique introns, indicating distinct evolutionary origins. They evolve at a rate ~ 10 to ~ 54 times slower compared to EpPAL1 and EpPAL4-7, suggesting strong purifying selection. EpPAL1 evolved independently and is another ancestral gene. EpPAL1 formed EpPAL4 through segmental duplication, which lead to EpPAL5 and EpPAL6 through tandem duplications, and EpPAL7 through transposed duplication, shaping modern EpPALs. Correlation analysis suggests EpPAL1, EpPAL2 and EpPAL3 play important roles in prenylated flavonol glycosides biosynthesis, with EpPAL2 and EpPAL3 strongly correlated with both Epimedin C and total prenylated flavonol glycosides. EpPAL1, EpPAL2 and EpPAL3 may play a role in anthocyanin biosynthesis in leaves. EpPAL2, EpPAL3, EpPAL6, and EpPAL7 might be engaged in anthocyanin production in petals, and EpPAL2 and EpPAL3 might also contribute to anthocyanin synthesis in sepals. Further experiments are needed to confirm these hypotheses. Novel insights into the evolution of PAL gene family suggest that it might have evolved from a monophyletic group in bryophytes to large-scale sequence differentiation in gymnosperms, basal angiosperms, and Magnoliidae. Ancestral gene duplications and vertical inheritance from gymnosperms to angiosperms likely occurred during PAL evolution. Most early-diverging eudicotyledons and monocotyledons have distinct histories, while modern angiosperm PAL gene families share similar patterns and lack distant gene types. CONCLUSIONS: EpPAL2 and EpPAL3 may play crucial roles in biosynthesis of prenylated flavonol glycosides and anthocyanins in leaves and flowers. This study provides novel insights into PAL gene family evolution. The findings on PAL genes in E. pubescens will aid in synthetic biology research on prenylated flavonol glycosides production.

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Amino acid (AA)-related inherited metabolic disorders (IMDs) and urea cycle disorders (UCDs) require strict dietary management including foods low in protein such as fruits, vegetables and starchy roots. Despite this recommendation, there are limited data on the AA content of many of these foods. The aim of this study is to describe an analysis of the protein and AA content of a range of fruits, vegetables and starchy roots, specifically focusing on amino acids (AAs) relevant to AA-related IMDs such as phenylalanine (Phe), methionine (Met), leucine (Leu), lysine (Lys) and tyrosine (Tyr). AA analysis was performed using high-performance liquid chromatography (HPLC) on 165 food samples. Protein analysis was also carried out using the Dumas method. Foods were classified as either 'Fruits', 'Dried fruits', 'Cruciferous vegetables', 'Legumes', 'Other vegetables' or 'Starchy roots'. 'Dried fruits' and 'Legumes' had the highest median values of protein, while 'Fruits' and 'Cruciferous vegetables' contained the lowest median results. 'Legumes' contained the highest and 'Fruits' had the lowest median values for all five AAs. Variations were seen in AA content for individual foods. The results presented in this study provide useful data on the protein and AA content of fruits, vegetables and starchy roots which can be used in clinical practice. This further expansion of the current literature will help to improve diet quality and metabolic control among individuals with AA-related IMDs and UCDs.

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The essential oil and ß-cyclodextrin inclusion complex was able to inhibit the growth of Penicillium digitatum, a damaging pathogen that causes green mold in citrus fruit. In this study, cinnamaldehyde-ß-cyclodextrin inclusion complex (ß-CDCA) for controlling citrus green mold was synthesized by the co-precipitation method. Characterization of ß-CDCA revealed that the aromatic ring skeleton of cinnamaldehyde (CA) was successfully embedded into the cavity of ß-CD to form the inclusion complex. ß-CDCA inhibited P. digitatum at a minimum inhibitory concentration (MIC) and minimum fungicidal concentration (MFC) of 4.0 g/L. FT-IR spectroscopy analysis, calcofluor white staining, extracellular alkaline phosphatase (AKP) activity and propidium iodide (PI) staining of hyphae morphology showed that ß-CDCA may damage the cell ultrastructure and membrane permeability of P. digitatum. The study further demonstrated that hydrogen peroxide (H2O2), malondialdehyde (MDA), and reactive oxygen species (ROS) markedly accumulated in 1/2 MIC ß-CDCA treated hyphae. This implied that ß-CDCA inhibited growth of P. digitatum by the triggering oxidative stress, which may have caused cell death by altering cell membrane permeability. In addition, in vivo results showed that ß-CDCA alone or combined with L-phenylalanine (L-PHe) displayed a comparable level to that of prochloraz. Therefore, ß-CDCA combined with L-PHe can thus be used as an eco-friendly preservative for the control green mold in postharvest citrus fruit.

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BACKGROUND: Stress hyperphenylalaninemia predicts elevated mortality rates in patients with acute decompensated heart failure (ADHF). This study investigated the metabolic pathways underlying this association and identified a unique metabolic phenotype underlying the association between stress hyperphenylalaninemia and adverse outcomes in ADHF. METHODS AND RESULTS: This was a retrospective cohort study. We enrolled 120 patients with ADHF in an intensive care unit (60 with a phenylalanine level ≥112 µM, 60 with a phenylalanine level <112 µM), and 30 controls. Plasma phenylalanine-derived metabolites were measured, and participants were evaluated for 30-day death. Patients with ADHF had extensive activations of the alternative pathways for metabolizing phenylalanine, leading to the levels of phenylalanine-derived downstream metabolites 1.5 to 6.1 times higher in patients with ADHF than in the controls (all P<0.001). Extensive dysregulation of these alternative pathways significantly increased phenylalanine levels and contributed to a distinct metabolic phenotype, characterized by increased phenylalanine, tyrosine, homogentisic acid, and succinylacetone levels but decreased benzoic acid and 3,4-dihydroxyphenylalanine levels. Throughout the 30-day follow-up period, 47 (39.2%) patients died. This distinct metabolic phenotype was associated with an increased mortality rate (odds ratio, 1.59 [95% CI, 1.27-1.99]; P<0.001). A multivariable analysis confirmed the independent association of this metabolic phenotype, in addition to phenylalanine and tyrosine levels, with 30-day death. CONCLUSIONS: In patients with ADHF, extensive dysregulation of the alternative pathways for metabolizing phenylalanine was correlated with stress hyperphenylalaninemia and a distinct metabolic phenotype on the phenylalanine-tyrosine-homogentisic acid-succinylacetone axis. Both stress hyperphenylalaninemia and metabolic dysregulation on this axis were associated with poor outcomes.

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BACKGROUND: Lifelong management of phenylketonuria (PKU) centers on medical nutrition therapy, including dietary phenylalanine (Phe) restriction in addition to Phe-free or low-Phe medical foods/protein substitutes. Studies have reported low bone mineral density (BMD) in mixed-age PKU populations, possibly related to long-term Phe restriction. Therefore, a meta-analysis investigating BMD specifically in adults with PKU was conducted. METHODS: Studies reporting BMD-related outcomes were identified from a systematic literature review evaluating somatic comorbidities experienced by adults with PKU on a Phe-restricted diet (searched February 1, 2022, updated November 1, 2023). Risk of study bias was assessed (Scottish Intercollegiate Guidelines Network checklists). The primary outcome of the meta-analysis was pooled mean BMD Z-scores of different bones. Secondary outcomes were the prevalence of low BMD Z-scores at pre-specified thresholds. Subgroup analyses of mean BMD Z-scores (decade of study publication, controlled versus uncontrolled blood Phe levels, gender) were conducted. RESULTS: BMD-related data from 4097 individuals across 10 studies rated as at least acceptable quality were included. Mean BMD Z-scores were statistically significantly lower compared with an age-matched control or reference (non-PKU) population, across bones, but still within the expected range for age (> -2.0): lumbar spine (seven studies, n = 304), -0.63 (95% confidence interval (CI): -0.74, -0.52); femoral neck (four studies, n = 170), -0.74 (95% CI: -1.25, -0.22); radius (three studies, n = 114), -0.77 (95% CI: -1.21, -0.32); total body (four studies, n = 157), -0.61 (95% CI: -0.77, -0.45). The small number of observations in the subgroup analyses resulted in a high degree of uncertainty, limiting interpretation. Estimated prevalence of BMD Z-scores ≤ -2.0 was 8% (95% CI: 5%, 13%; four studies, n = 221) and < -1.0 was 42% (95% CI: 35%, 51%; five studies, n = 144). CONCLUSIONS: Adults with PKU had lower BMD Z-scores than the reference (non-PKU) population but < 1 in 10 were below the expected range for age. The low number of studies prevents identification of which population characteristics are most impacting BMD. This meta-analysis was supported by BioMarin Pharmaceutical Inc., Novato, CA and is registered with the Research Registry (reviewregistry1476).

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L-Phenylalanine (L-Phe) is an important aromatic amino acid, which has been widely used in food, health care products, medicine and other fields. Based on the relatively mature microbial biosynthesis process, a variety of L-phenylalanine-derived compounds have attracted more and more attentions owing to their extensively potential applications in the fields of food, medicine, spices, cosmetics, and pesticides. However, the challenge of biosynthesis of L-phenylalanine-derived compounds remains the issue of low production and productivity. With the development of metabolic engineering and synthetic biology, the biosynthesis of L-phenylalanine has reached a high level. Therefore, the synthesis of L-phenylalanine-derived compounds based on high production strains of L-phenylalanine has broad prospects. In addition, some L-phenylalanine-derived compounds are more suitable for efficient synthesis by exogenous addition of precursors due to their longer metabolic pathways and the inhibitory effects of many intermediate products. This review systematically summarized the research progress of L-phenylalanine-derived compounds, including phenylpyruvate derivatives, trans-cinnamic derivatives, p-coumaric acid derivatives and other L-phenylalanine-derived compounds (such as flavonoids). Finally, the main strategies to improve the production of L-phenylalanine-derived compounds were summarized, and the development trends of the synthesis of L-phenylalanine-derived compounds by microbial method were also prospected.

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Hepatitis C virus (HCV) is a global health concern and the NS5B RNA-dependent RNA polymerase (RdRp) of HCV is an attractive target for drug discovery due to its role in viral replication. This study focuses on NS5B thumb site II inhibitors, specifically phenylalanine derivatives, and explores bioisosteric replacement and prodrug strategies to overcome limitations associated with carboxylic acid functionality. The synthesized compounds demonstrated antiviral activity, with compound 6d showing the most potent activity with an EC50 value of 3.717 µM. The hydroxamidine derivatives 7a-d showed EC50 values ranging from 3.9 µM to 11.3 µM. However, the acidic heterocyclic derivatives containing the oxadiazolone (8a-d) and oxadiazolethione (9a-d) rings did not exhibit measurable activity. A methylated heterocycle 10b showed a hint of activity at 8.09 µM. The pivaloyloxymethyl derivatives 11a and 11b did not show antiviral activity. Further studies are warranted to fully understand the effects of these modifications and to explore additional strategies for developing novel therapeutic options for HCV.

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This study aimed to investigate the surface hardness, monomer conversion, surface roughness, boron release, and water sorption-solubility properties of experimental resin composites (RC) containing hydroxyapatite nanocarriers (HAP) loaded with different boron compounds, in comparison to a conventional RC. In this study, boron nitride and 4-borono-L-phenylalanine were loaded into mesoporous and nonporous HAP. 1% boron-nanocarrier complexes were added to a conventional resin-composite content. The study groups were designated based on the boron compound and nanocarrier type: Group 1 (Control): (a conventional RC), Group 2: Experimental RC containing mesoporous HAP loaded with boron nitride (BN@MHAP), Group 3: Experimental RC containing nonporous HAP loaded with boron nitride (BN@HAP), Group 4: Experimental RC containing mesoporous HAP loaded with 4-borono-L-phenylalanine (BPA@MHAP), Group 5: Experimental RC containing nonporous HAP loaded with 4-borono-L-phenylalanine (BPA@HAP). Vickers microhardness, surface roughness, degree of monomer conversion, water sorption-solubility, and boron release analyses were conducted on the RC samples. The nanoparticles were characterized using the Energy Dispersive X-ray Spectroscopy (EDX) for elemental analysis and mapping, X-ray Diffraction (XRD) for examining crystal structure, Fourier-Transform Infrared Spectroscopy (FTIR) for evaluating molecular bond structure, and Scanning Electron Microscopy (SEM) for observing surface morphology of mesoporous and non-porous HAP. No statistically significant difference was found between the experimental RC materials containing boron-nanocarrier complexes and the control group in terms of monomer conversion, surface hardness, surface roughness, water sorption and solubility (p > 0.05). However, all experimental groups demonstrated significantly higher boron release rates over time (p < 0.05), with BN@HAP and BPA@MHAP groups exhibiting the highest release rates at all timepoints (p < 0.05). The addition of 1% BN@HAP/MHAP or BPA@HAP/MHAP to the RC is promising for developing an antibacterial RC capable of releasing boron without compromising the tested physico-chemical properties of the material.

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To deal with complicated separation situations, this study successfully prepared two mixed-mode chromatography (MMC) stationary phases, CCL-SIL and PCL-SIL, by functionalizing dialdehyde cellulose (DAC) derivatives. In liquid chromatography applications, CCL-SIL exhibited superior separation performance for nucleosides and bases in HILIC mode, while PCL-SIL performed better in RPLC and IEC modes. Their distinct separation mechanisms were also elucidated by quantum chemical calculations. Both CCL-SIL and PCL-SIL showed good stability and reproducibility, with relative standard deviations of retention time, peak area, and peak height below 7.79 % and 4.37 % for multiple injections. Particularly, the PCL-SIL column and the CCL-SIL column were successfully used for the quantitative analysis of trace targets in real samples with complex matrix, demonstrating high accuracy and precision.

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In phenylketonuria (PKU), natural protein intake is thought to increase with age, particularly during childhood and adolescence. Longitudinal dietary intake data are scarce and lifelong phenylalanine tolerance remains unknown. Nine centres managing PKU in Europe and Turkey participated in a retrospective study. Data were collected from dietetic records between 2012 and 2018 on phenylalanine (Phe), natural protein, and protein substitute intake. A total of 1323 patients (age range: 1-57 y; 51% male) participated. Dietary intake data were available on 1163 (88%) patients. Patient numbers ranged from 59 to 320 in each centre. A total of 625 (47%) had classical PKU (cPKU), n = 357 (27%) had mild PKU (mPKU), n = 325 (25%) had hyperphenylalaninemia (HPA), and n = 16 (1%) were unknown. The mean percentage of blood Phe levels within target ranged from 65 ± 54% to 88 ± 49%. When intake was expressed as g/day, the mean Phe/natural protein and protein equivalent from protein substitute gradually increased during childhood, reaching a peak in adolescence, and then remained consistent during adulthood. When intake was expressed per kg body weight (g/kg/day), there was a decline in Phe/natural protein, protein equivalent from protein substitute, and total protein with increasing age. Overall, the mean daily intake (kg/day) was as follows: Phe, 904 mg ± 761 (22 ± 23 mg/kg/day), natural protein 19 g ± 16 (0.5 g/kg/day ± 0.5), protein equivalent from protein substitute 39 g ± 22 (1.1 g/kg/day ± 0.6), and total protein 59 g ± 21 (1.7 g/kg/day ± 0.6). Natural protein tolerance was similar between males and females. Patients with mPKU tolerated around 50% less Phe/natural protein than HPA, but 50% more than cPKU. Higher intakes of natural protein were observed in Southern Europe, with a higher prevalence of HPA and mPKU compared with patients from Northern European centres. Natural protein intake doubled with sapropterin usage. In sapropterin-responsive patients, 31% no longer used protein substitutes. Close monitoring and optimisation of protein intake prescriptions are needed, along with future guidelines specifically for different age groups and severities.

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Backgrounds: Atrial fibrillation (AF) is a common complication of chronic heart failure (HF). Serum phenylalanine (Phe) levels are related to inflammation disorder. It is meaningful to study the circulating Phe with AF occurrence in HF. Methods: The cross-sectional study recruited 300 patients (78.0% male; mean age, 65 ± 13 years) with HF (left ventricular ejection fraction of ≤50%, containing 70 AF patients) and 100 normal controls. Serum Phe value was measured by liquid chromatography-tandem mass spectrometry. Logistic regression analysis was conducted to measure the association between Phe and AF risk in HF. The association between Phe and high-sensitivity C-reactive protein (hsCRP) was assessed by simple correlation analysis. In the prospective study, the 274 HF subjects (76.6% male; mean age, 65 ± 13 years) were followed up for a mean year (10.99 ± 3.00 months). Results: Serum Phe levels increased across the control, the HF without AF, and the HF with AF groups (77.60 ± 8.67 umol/L vs. 95.24 ± 28.58 umol/L vs. 102.90 ± 30.43 umol/L, ANOVA P < 0.001). Serum Phe value was the independent risk factor for predicting AF in HF [odds ratio (OR), 1.640; 95% CI: 1.150-2.339; P = 0.006]. Phe levels were correlated positively with hsCRP value in HF patients with AF (r = 0.577, P < 0.001). The elevated Phe levels were associated with a higher risk of HF endpoint events in HF patients with AF (log-rank P = 0.005). Conclusions: In HF with AF subjects, elevated Phe value confers an increased risk for prediction AF and was more related to poor HF endpoint events. Phe can be a valuable index of AF in HF.

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Phenylketonuria is a rare inherited disorder that disrupts the metabolism of phenylalanine (Phe) to tyrosine by phenylalanine hydroxylase (PAH). Sapropterin dihydrochloride (Kuvan®) is approved for use in Europe to reduce blood Phe levels and improve Phe tolerance in sapropterin-responsive individuals. KAMPER (NCT01016392) is an observational, multinational registry assessing long-term safety and efficacy of sapropterin. Five hundred and seventy-six participants with PAH deficiency were enrolled from nine European countries (69 sites; December 2009-May 2016). Participants were aged <4 years (n = 11), 4 to <12 years (n = 329), 12 to <18 years (n = 141), and ≥18 years (n = 95) at enrolment. Overall, 401 (69.6%) participants experienced a total of 1960 adverse events; 61 events in 42 participants were serious, and two were considered sapropterin-related by the investigator. Mean (standard deviation) actual dietary Phe intake increased from baseline across all age groups: 957 (799) mg/day to a maximum of 1959 (1121) mg/day over a total study period of 11 years. Most participants exhibited an increase in Phe tolerance while blood Phe levels remained in the target range for their age (120-360 µmol/L for <12 years; 120-600 µmol/L for ≥12 years). Most participants exhibited normal growth for height, weight, and body mass index. No additional safety concerns were identified. As an observational study, limitations include variability in routine care practices and inconsistent availability of data. Long-term sapropterin use demonstrates a favourable safety profile in real-world settings and increases Phe tolerance in participants with PAH deficiency while maintaining blood Phe levels in the target ranges.

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Human papillomavirus (HPV) L1 capsid protein were produced in several host systems, but few studies have focused on enhancing the properties of the L1 protein. In this study, we aimed to produce recombinant Human papillomavirus (HPV) L1 capsid protein containing para-azido-L-phenylalanine (pAzF) in Escherichia coli. First, we expressed the maltose-binding protein (MBP)- fused HPV16 L1, and 5 residues in HPV16 L1 protein were selected by the in silico modeling for amber codon substitution. Among the variants of the five locations, we identified a candidate that exhibited significant differences in expression with and without pAzF via genetic code expansion (GCE). The expressed recombinant MBP-HPV16L1 protein was confirmed for incorporation of pAzF and the formation of VLPs was tested in vitro.

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BACKGROUND: Phenylketonuria (PKU) is an inborn error of phenylalanine (Phe) metabolism that, if untreated, causes Phe accumulation in the brain leading to neurophysiologic alterations and poor outcomes. Lifelong management centers on dietary Phe restriction, yet long-term complete metabolic control is unachievable for many adults. High blood Phe levels or chronic Phe and intact protein restriction in the diet may lead to somatic comorbidities. A systematic literature review was conducted to evaluate somatic comorbidities experienced by adults with PKU. METHODS: Clinical and observational studies reporting somatic comorbidities experienced by individuals with PKU aged ≥ 16 years (or classified as adults) evaluating a Phe-restricted diet with or without pharmacologic therapy versus no therapeutic intervention (including healthy controls), or pharmacologic therapy versus a Phe-restricted diet alone, were identified. PubMed® was searched (February 1, 2022 and updated November 1, 2023), using a pre-defined search strategy, followed by two-stage screening and data extraction. Included studies were grouped by PKU population comparison. RESULTS: 1185 records were screened; 51 studies across 12,602 individuals were extracted. Bone-related abnormalities were the most reported outcome (n = 21); several outcome measures were used. Original study groupings included: Phe-restricted diet versus healthy controls or reference values (n = 40); treatment-adherent versus those non-adherent (n = 12). Additional groups added as part of a protocol amendment included: different Phe-restricted diets (n = 4); severe versus less severe disease (n = 5). Vote counting indicated a higher burden of ≥ 1 comorbidity (or outcome measure) for the Phe-restricted diet group by 37 of 38 studies included in the analysis of Phe-restricted diet versus healthy controls; higher burden in healthy controls was reported in 12 studies. Vote counting was similar between those treatment adherent (n = 7) versus non-adherent (n = 10). CONCLUSIONS: Adults with PKU have a higher comorbidity burden than a non-PKU population. More robust studies are needed to better understand the relationship between effective metabolic control and comorbidity burden, using consistent outcome measures. This SLR was supported by BioMarin Pharmaceutical Inc., Novato, CA, and is registered with the Research Registry (reviewregistry1476).

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Molecularly imprinted silica nanoparticles (SP-MIP) are synthesized for the real-time optical detection of low-molecular-weight compounds. Azo-initiator-modified silica beads are functionalized through reversible addition-fragmentation chain transfer (RAFT) polymerization, which leads to efficient control of the grafted layer. The copolymerization of methacrylic acid (MAA) and ethylene glycol dimethacrylate (EDMA) on azo initiator-coated silica particles (≈100 nm) using chain transfer agent (2-phenylprop-2-yl-dithiobenzoate) is carried out in the presence of a target analyte molecule (l-Boc-phenylalanine anilide, l-BFA). The chemical and morphological properties of SP-MIP are characterized by scanning electron microscopy, X-ray photoelectron spectroscopy, Brunauer-Emmett-Teller surface analysis, and thermogravimetric analysis. Finally, SP-MIP is located on the gold surface to be used as a biorecognition layer on the surface plasmon resonance spectrometer (SPR). The sensitivity, response time, and selectivity of SP-MIP are investigated by three similar analogous molecules (l-Boc-Tryptophan, l-Boc-Tyrosine, and l-Boc-Phenylalanine) and the imprinted particle surface showed excellent relative selectivity toward l-Boc-Phenylalanine (l-BFA) (k = 61), while the sensitivity is recorded as limit of detection = 1.72 × 10-4 m.