Classical swine fever virus non-structural protein 5B hijacks host METTL14-mediated m6A modification to counteract host antiviral immune response.

Classical Swine Fever (CSF), caused by the Classical Swine Fever Virus (CSFV), inflicts significant economic losses on the global pig industry. A key factor in the challenge of eradicating this virus is its ability to evade the host's innate immune response, leading to persistent infections. In our study, we elucidate the molecular mechanism through which CSFV exploits m6A modifications to circumvent host immune surveillance, thus facilitating its proliferation. We initially discovered that m6A modifications were elevated both in vivo and in vitro upon CSFV infection, particularly noting an increase in the expression of the methyltransferase METTL14. CSFV non-structural protein 5B was found to hijack HRD1, the E3 ubiquitin ligase for METTL14, preventing METTL14 degradation. MeRIP-seq analysis further revealed that METTL14 specifically targeted and methylated TLRs, notably TLR4. METTL14-mediated regulation of TLR4 degradation, facilitated by YTHDF2, led to the accelerated mRNA decay of TLR4. Consequently, TLR4-mediated NF-κB signaling, a crucial component of the innate immune response, is suppressed by CSFV. Collectively, these data effectively highlight the viral evasion tactics, shedding light on potential antiviral strategies targeting METTL14 to curb CSFV infection.

Structure of the human metapneumovirus polymerase phosphoprotein complex.

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause severe respiratory diseases in infants and elderly adults1. No vaccine or effective antiviral therapy currently exists to control RSV or HMPV infections. During viral genome replication and transcription, the tetrameric phosphoprotein P serves as a crucial adaptor between the ribonucleoprotein template and the L protein, which has RNA-dependent RNA polymerase (RdRp), GDP polyribonucleotidyltransferase and cap-specific methyltransferase activities2,3. How P interacts with L and mediates the association with the free form of N and with the ribonucleoprotein is not clear for HMPV or other major human pathogens, including the viruses that cause measles, Ebola and rabies. Here we report a cryo-electron microscopy reconstruction that shows the ring-shaped structure of the polymerase and capping domains of HMPV-L bound to a tetramer of P. The connector and methyltransferase domains of L are mobile with respect to the core. The putative priming loop that is important for the initiation of RNA synthesis is fully retracted, which leaves space in the active-site cavity for RNA elongation. P interacts extensively with the N-terminal region of L, burying more than 4,016 Å2 of the molecular surface area in the interface. Two of the four helices that form the coiled-coil tetramerization domain of P, and long C-terminal extensions projecting from these two helices, wrap around the L protein in a manner similar to tentacles. The structural versatility of the four P protomers-which are largely disordered in their free state-demonstrates an example of a 'folding-upon-partner-binding' mechanism for carrying out P adaptor functions. The structure shows that P has the potential to modulate multiple functions of L and these results should accelerate the design of specific antiviral drugs.

Supramolecular Mimotope Peptide Nanofibers Promote Antibody-Ligand Polyvalent and Instantaneous Recognition for Biopharmaceutical Analysis.

Peptide-based supramolecules exhibit great potential in various fields due to their improved target recognition ability and versatile functions. However, they still suffer from numerous challenges for the biopharmaceutical analysis, including poor self-assembly ability, undesirable ligand-antibody binding rates, and formidable target binding barriers caused by ligand crowding. To tackle these issues, a "polyvalent recognition" strategy employing the CD20 mimotope peptide derivative NBD-FFVLR-GS-WPRWLEN (acting on the CDR domains of rituximab) was proposed to develop supramolecular nanofibers for target antibody recognition. These nanofibers exhibited rapid self-assembly within only 1 min and robust stability. Their binding affinity (179 nM) for rituximab surpassed that of the monomeric peptide (7 µM) by over 38-fold, highlighting that high ligand density and potential polyvalent recognition can efficiently overcome the target binding barriers of traditional supramolecules. Moreover, these nanofibers exhibited an amazing "instantaneous capture" rate (within 15 s), a high recovery (93 ± 3%), and good specificity for the target antibody. High-efficiency enrichment of rituximab was achieved from cell culture medium with good recovery and reproducibility. Intriguingly, these peptide nanofibers combined with bottom-up proteomics were successful in tracking the deamidation of asparagine 55 (from 10 to 16%) on the rituximab heavy chain after 21 day incubation in human serum. In summary, this study may open up an avenue for the development of versatile mimotope peptide supramolecules for biorecognition and bioanalysis of biopharmaceuticals.

Regulation of seed soaking with indole-3-butyric acid potassium salt (IBA-K) on rapeseed (Brassica napus L.) seedlings under NaCl stress.

The growth and yield of rapeseed are significantly hampered by salt stress. Indole-3-butyric Acid Potassium Salt (IBA-K) has been found to alleviate the impact of salt stress on plant growth. However, the regulatory effect of IBA-K dipping on salt-stressed rapeseed remains unclear. To explore the implications of IBA-K on the growth and development of rapeseed during the seedling stage, we conducted potting experiments using the Huayouza 62 variety. Five different concentrations of IBA-K for seed soaking (0, 10, 20, 40, 80 mg·L- 1) were tested. The promotional impact of IBA-K on rapeseed demonstrated an initial increase followed by a decline, reaching a peak at 20 mg·L- 1. Therefore, 20 mg·L- 1 was determined as the optimal concentration for subsequent experiments. To further understand the mechanism of IBA-K's action on salt-stressed rapeseed seedlings, we utilized the moderately salt-resistant cabbage rapeseed variety Huayouza 158R and the highly salt-resistant Huayouza 62 as specimens. The investigation focused on their response and repair mechanisms under 150 mmol·L- 1 NaCl stress. The findings demonstrated that compared with the sole NaCl stress, the 20 mg·L- 1 IBA-K seed soaking treatment under salt stress significantly enhanced the plant height, stem diameter, and leaf area of both rapeseed varieties. It also led to greater biomass accumulation, increased chlorophyll content, and improved photosynthetic efficiency in rapeseed. Furthermore, this treatment bolstered the activity of antioxidant enzymes such as superoxide dismutase (SOD), peroxidase (POD), and catalase (CAT), while significantly reducing the levels of electrolyte leakage (EL) and malondialdehyde (MDA). Consequently, it alleviated the membrane lipid peroxidation damage induced by NaCl stress, enhanced the accumulation of soluble proteins, maintained cellular osmotic pressure, and effectively mitigated the adverse effects of NaCl stress on rapeseed.

Cellular ESCRT components are recruited to regulate the endocytic trafficking and RNA replication compartment assembly during classical swine fever virus infection.

As the important molecular machinery for membrane protein sorting in eukaryotic cells, the endosomal sorting and transport complexes (ESCRT-0/I/II/III and VPS4) usually participate in various replication stages of enveloped viruses, such as endocytosis and budding. The main subunit of ESCRT-I, Tsg101, has been previously revealed to play a role in the entry and replication of classical swine fever virus (CSFV). However, the effect of the whole ESCRT machinery during CSFV infection has not yet been well defined. Here, we systematically determine the effects of subunits of ESCRT on entry, replication, and budding of CSFV by genetic analysis. We show that EAP20 (VPS25) (ESCRT-II), CHMP4B and CHMP7 (ESCRT-III) regulate CSFV entry and assist vesicles in transporting CSFV from Clathrin, early endosomes, late endosomes to lysosomes. Importantly, we first demonstrate that HRS (ESCRT-0), VPS28 (ESCRT-I), VPS25 (ESCRT-II) and adaptor protein ALIX play important roles in the formation of virus replication complexes (VRC) together with CHMP2B/4B/7 (ESCRT-III), and VPS4A. Further analyses reveal these subunits interact with CSFV nonstructural proteins (NS) and locate in the endoplasmic reticulum, but not Golgi, suggesting the role of ESCRT in regulating VRC assembly. In addition, we demonstrate that VPS4A is close to lipid droplets (LDs), indicating the importance of lipid metabolism in the formation of VRC and nucleic acid production. Altogether, we draw a new picture of cellular ESCRT machinery in CSFV entry and VRC formation, which could provide alternative strategies for preventing and controlling the diseases caused by CSFV or other Pestivirus.

Copper-Catalyzed P-H Bond Functionalization to Construct Biaryl Phosphafluorene Oxides.

In this study, in the presence of a certain amount of cuprous chloride catalyst and the synergistic action of ligand and base, the P-H bond activation of secondary biarylphosphine oxides and the attack on the ß-site of orthoaryl groups were investigated. Phosphafluorene oxide was synthesized by C-H bond activation and an intramolecular dehydrogenation coupling reaction to construct a C-P bond. Subsequently, we conducted a control experiment and made reasonable speculations about its mechanism. In addition, the use of phosphafluorene as a ligand in some synthetic catalytic reactions has shown excellent results, demonstrating its excellent catalytic properties.

Photomediated One-Pot Three-Component Approach Enables the Formal Direct N-Acylation/Sulfonylation and α-C-H Functionalization of 1,2,3,4-Tetrahydroisoquinoline.

N-Acyl/sulfonyl-α-functionalized 1,2,3,4-tetrahydroisoquinolines (THIQs) are significant structural motifs in organic synthesis and drug discovery. However, the one-pot approach enabling direct difunctionalization of THIQs remains challenging. Herein we report a photomediated one-pot three-component strategy to access N-acyl/sulfonyl-α-functionalized THIQs. This method features the use of oxygen (from air) as the green oxidant, high atom and step economy, and decent structural diversity. The synthetic applicability of the method was further demonstrated via the facile construction of valuable bioactive molecules. Mechanistic studies indicated that oxidation with singlet oxygen and the acceptor-less dehydrogenation were involved in the photoredox process.

HflX is a GTPase that controls hypoxia-induced replication arrest in slow-growing mycobacteria.

GTPase high frequency of lysogenization X (HflX) is highly conserved in prokaryotes and acts as a ribosome-splitting factor as part of the heat shock response in Escherichia coli. Here we report that HflX produced by slow-growing Mycobacterium bovis bacillus Calmette-Guérin (BCG) is a GTPase that plays a critical role in the pathogen's transition to a nonreplicating, drug-tolerant state in response to hypoxia. Indeed, HflX-deficient M. bovis BCG (KO) replicated markedly faster in the microaerophilic phase of a hypoxia model that resulted in premature entry into dormancy. The KO mutant displayed hallmarks of nonreplicating mycobacteria, including phenotypic drug resistance, altered morphology, low intracellular ATP levels, and overexpression of Dormancy (Dos) regulon proteins. Mice nasally infected with HflX KO mutant displayed increased bacterial burden in the lungs, spleen, and lymph nodes during the chronic phase of infection, consistent with the higher replication rate observed in vitro in microaerophilic conditions. Unlike fast growing mycobacteria, M. bovis BCG HlfX was not involved in antibiotic resistance under aerobic growth. Proteomics, pull-down, and ribo-sequencing approaches supported that mycobacterial HflX is a ribosome-binding protein that controls translational activity of the cell. With HflX fully conserved between M. bovis BCG and M. tuberculosis, our work provides further insights into the molecular mechanisms deployed by pathogenic mycobacteria to adapt to their hypoxic microenvironment.

Inhibitory interaction of flavonoids with organic anion transporter 3 and their structure-activity relationships for predicting nephroprotective effects.

The organic anion transporter 3 (OAT3), an important renal uptake transporter, is associated with drug-induced acute kidney injury (AKI). Screening and identifying potent OAT3 inhibitors with little toxicity in natural products, especially flavonoids, in reducing OAT3-mediated AKI is of great value. The five strongest OAT3 inhibitors from the 97 flavonoids markedly decreased aristolochic acid I-induced cytotoxicity and alleviated methotrexate-induced nephrotoxicity. The pharmacophore model clarified hydrogen bond acceptors and hydrophobic groups are the critical pharmacophores. These findings would provide valuable information in predicting the potential risks of flavonoid-containing food/herb-drug interactions and optimizing flavonoid structure to alleviate OAT3-related AKI.

High spatial variability in a species-rich assemblage of diadromous fishes in Hong Kong, southern China.

China has experienced substantial coastal reclamation and damming of rivers. These changes have the potential to impact migrations of diadromous fishes between the sea and fresh waters, but the composition of these fishes and the impacts of barriers to their movement in China have received little attention. We inventoried the species composition and distribution of diadromous fishes, and the impacts of barriers on them, in the Hong Kong Special Administrative Region (HKSAR), southern China. Fish assemblages were surveyed using hand-nets, supplemented by cast-netting and single-pass snorkel surveys, in 24 small coastal streams across three regions. Surveys were undertaken on multiple occasions during the wet and dry seasons to account for the monsoonal tropical climate. Twenty-eight diadromous fishes were collected, mostly gobies, amounting to over half (53%) of the total richness of primary freshwater fishes; four additional species are known from literature records. Diadromous richness was 48% greater during the wet season, when all species were encountered. Richness varied substantially among streams, from a maximum of 17 (2 streams that were diversity hot spots) to none (3 streams). The most widespread diadromous fish was Glossogobius giuris (71% frequency of occurrence), followed by Mugil cephalus (58% occurrence) and Eleotris oxycephala (50% occurrence). The remaining 25 diadromous fishes occurred in fewer than half of the streams; 12 species were confined to a single stream and may be locally threatened. There were conspicuous spatial differences in diadromous assemblages across HKSAR, despite its limited extent (1114 km2), the proximity of the surveyed streams, and the broad geographic distribution of most species. Regional species assemblages were influenced by localized habitat characteristics, with a noticeable distinction between areas with and without large, fast-flowing, and highly oxygenated streams. The presence of in-stream barriers (weirs: 0.3-8.7 m high) did not affect spatial patterns in species assemblages, although, on average, diadromous richness was lower in weir-obstructed streams (4.0 vs. 6.9 species in unobstructed streams). In total, 18 species were confined to unobstructed streams or sections below weirs, whereas the remaining 10 species were recorded both above and below weirs. Only the mottled eel (Anguilla marmorata) and a goby (Stiphodon multisquamus) were able to ascend weirs over 2 m. Although at least 400 m of the lower course of each stream was sampled, diadromous fishes were confined to the first 300 m in 12 of the 13 weir-obstructed streams. Remarkably, the tally of 32 diadromous species in HKSAR exceeds the 19 known from mainland China, highlighting the need for further research on composition and conservation status of diadromous fishes.

Functional teeth and cognitive function among the Chinese elderly: The chain mediating effect of depressive symptoms and social participation.

The objective of this study was to investigate the chain mediating effects of depressive symptoms and social participation between functional teeth and cognitive function based on the biopsychosocial model. Data from the 2018 China Health and Retirement Longitudinal Study were analyzed. The findings revealed a favorable connection between the lack of edentulism and cognitive function, persisting even when accounting for the mediating factors of denture usage, depressive symptoms, and social participation. Furthermore, the study identified six indirect pathways in this relationship. The present study has substantiated the correlation between edentulism and cognitive function, thereby proposing that interventions aimed at denture usage, depressive symptoms, and social participation could potentially serve as preventive measures against cognitive decline in elderly individuals afflicted with edentulism. This underscores the significance of addressing these factors to alleviate cognitive decline.

Simultaneous Bilateral Cochlear Implantation in Very Young Children Improves Adaptability and Social Skills: A Prospective Cohort Study.

OBJECTIVES: To investigate the value of using the Gesell Development Diagnosis Scale (GDDS) to predict developmental outcomes in very young children who undergo simultaneous bilateral cochlear implantation. DESIGN: In this prospective cohort study, a repeated-measures investigation was conducted in a tertiary referral hospital. A total of 62 children receiving simultaneous bilateral cochlear implantations were enrolled from April 2017 to August 2018. They were divided into 2 groups depending on the operative age: "Infants" group (6 to 12 months, N = 38) or "Children" group (12 to 36 months, N = 24). Data on the surgical outcomes, auditory development, speech production, and developmental indicators were collected until 2 years after the initial fitting. The primary outcome measure was the GDDS, a neuropsychological development examination. Secondary outcomes included the following: complication rate, aided pure-tone average, Infant-Toddler Meaningful Auditory Integration Scale, Categories of Auditory Performance-II, Meaningful Use of Speech Scale, Speech Intelligibility Rating, and the LittlEARS Auditory Questionnaire. RESULTS: The mean ages at implantation in infants and children groups were 9.2 ± 1.17 and 16.6 ± 3.60 months, respectively. Significant differences were found in the social skills ( p = 0.001) and adaptability ( p = 0.031) domains of GDDS. The younger the age of bilateral cochlear implants surgery, the higher developmental quotient of language, social skills, and adaptability the child could achieve after 2 years. The complication rates in the infants and children groups were 0% versus 2.1% ( p = 0.57). There was no surgical complication in the infants group. In the children group, 1 case with enlarged vestibular aqueduct and Mondini malformation had a receiver-implant misplacement on the right side (2%, 1/48). In the two groups, auditory performance and speech production had improved similarly. In the infants group, social skills developmental quotient at baseline had a significant positive relationship with Meaningful Use of Speech Scale after 2 years. CONCLUSIONS: Simultaneous bilateral cochlear implantation in younger children improves adaptability and social skills. GDDS is a sensitive tool of evaluating short-term effect of bilateral cochlear implants in neuropsychological development and constitutes a reliable predictor of speech production for the very younger pediatric cochlear implant users.

Understanding the experiences of mothers receiving perinatal palliative care: A qualitative study.

BACKGROUND: Despite the diagnosis of life-limiting foetal conditions, some mothers choose to continue their pregnancies. The experiences of these individuals are relatively unknown, making it difficult for perinatal palliative services to be targeted towards their needs. AIM: To examine maternal experiences in perinatal palliative care among those who choose to continue their pregnancies despite life-limiting foetal condition. DESIGN: Qualitative, retrospective study involving semi-structured interviews. Braun & Clarke's reflexive thematic analyses using a constructionist-interpretive approach were conducted. SETTING/PARTICIPANTS: A total of 15 adult women participants who decided to continue their pregnancies after learning of life-limiting foetal diagnoses were recruited from a Singaporean tertiary hospital. Interviews were conducted in-person or via video conferencing. RESULTS: Seven themes were synthesized from the data: (1) Internal upheaval - 'World turns upside down'; (2) Role of religion and spirituality in hope of miracles; (3) Support from family and close friends; (4) Navigating a fragmented healthcare system; (5) Value added by the perinatal palliative service; (6) Goodbye and grieving and (7) No regrets and other personal reflections. CONCLUSIONS: Continuing a pregnancy despite the diagnosis of a life-limiting foetal condition can be challenging for mothers. To better meet their needs during this difficult period, perinatal palliative care must be patient-centred, multidisciplinary and non-judgmental. Efforts must be made to streamline the healthcare delivery process.

[Analysis and evaluation of bioactive constituents from different parts of Epimedium brevicornum].

A comprehensive analytical method based on ultra-fast liquid chromatography coupled with triple quadrupole/linear ion trap tandem mass spectrometry(UFLC-QTRAP-MS/MS) was established for simultaneous determination of the content of 45 bioactive constituents including flavonoids, alkaloids, amino acids, phenolic acids, and nucleosides in Epimedium brevicornum. The multiple bioactive constituents in leaves, petioles, stems and rhizomes of E. brevicornum were analyzed. The gradient elution was performed at 30 ℃ in an XBridge~® C_(18) column(4.6 mm×100 mm, 3.5 µm) with 0.4% formic acid aqueous solution-acetonitrile as the mobile phase at a flow rate of 0.8 mL·min~(-1). Single factor experiment and response surface methodology were employed to optimize the extraction conditions. Multivariate statistical analyses including systematic cluster analysis(SCA), principal component analysis(PCA), partial least squares discriminant analysis(PLS-DA), and one-way analysis of variance(One-way ANOVA) were carried out to classify the samples from different parts and identify different constituents. Grey relation analysis(GRA) and entropy weight-TOPSIS analysis were performed to build a multi-index comprehensive evaluation model for different parts of E. brevicornum. The results showed that there was a good relationship between the mass concentrations of 45 constituents and the corresponding peak areas, with the correlation coefficients(r) not less than 0.999 0. The precision, repeatability, and stability of the established method were good for all the target constituents in this study, with the relative standard deviations(RSDs) less than 5.0%(0.62%-4.9%) and the average recovery of 94.51%-105.7%. The above results indicated that the bioactive constituents varied in different parts of E. brevicornum, and the overall quality followed the trend of leaves > petioles > rhizomes > stems. This study verified the rationality of the Chinese Pharmacopoeia(2020 edition) stipulating that the medicinal part of E. brevicornum is the leaf. Moreover, our study indicated that the rhizome had the potential for medicinal development. The established method was accurate and reliable, which can be used to comprehensive evaluate and control the quality of E. brevicornum. This study provides data reference for clarifying the medicinal parts and rationally utilizing the resources of E. brevicornum.

[Quality evaluation of Lysimachiae Herba from different habitats based on simultaneous determination of multiple bioactive constituents combined with multivariate statistical analysis].

A method based on ultra-high performance liquid chromatography coupled with triple quadrupole linear ion trap-tandem mass spectrometry(UHPLC-QTRAP-MS/MS) was developed for the simultaneous determination of 41 bioactive constituents of flavonoids, organic acids, nucleosides, and amino acids in Lysimachiae Herba. The content of multiple bioactive constituents was compared among the samples from different habitats. The chromatographic separation was performed in a Waters XBridge®C_(18) column(4.6 mm×100 mm, 3.5 µm) at 30 ℃. The gradient elution was performed with 0.4% methanol(A)-formic acid water(B) as the mobile phase at a flow rate of 0.8 mL·min~(-1), and the multiple-reaction monitoring(MRM) mode was adopted. According to the content of 41 constituents, hierarchical cluster analysis(HCA), orthogonal partial least squares discriminant analysis(OPLS-DA), and gray relational analysis(GRA) were perfomed to comprehensively evaluate the samples from different habitats. The results showed that the 41 constituents exhibited good linear relationship within the tested concentration ranges, with the correlation coefficients(r) greater than 0.999 4. The method featured good precision, repeatability, and stability with the relative standard deviations(RSDs) less than 5.0%. The average recoveries of the 41 constituents ranged from 98.06% to 101.9%, with the RSDs of 0.62%-4.6%. HCA and OPLS-DA separated 48 batches of Lysimachiae Herba samples from different habitats into three categories: the producing areas in Sichuan and Chongqing, the producing areas in Jiangsu, Zhejiang, and Jiangxi, and the producing areas in Guizhou. The content of 41 constituents varied among the Lysimachiae Herba samples from different habitats. The GRA results revealed that the Lysimachiae Herba sample from Nanchong City, Sichuan Province had the best comprehensive quality. The method developed in this study was accurate and reliable and thus can be used for comprehensive evaluation of Lysimachiae Herba quality and provide basic information for the selection of habitats.

Copper-Catalyzed Enantioconvergent Radical C(sp3 )-N Cross-Coupling: Access to α,α-Disubstituted Amino Acids.

Transition-metal catalyzed enantioconvergent cross-coupling of tertiary alkyl halides with ammonia offers a rapid avenue to chiral unnatural α,α-disubstituted amino acids. However, the construction of chiral C-N bonds between tertiary-carbon electrophiles and nitrogen nucleophiles presented a great challenge owing to steric congestion. We report a copper-catalyzed enantioconvergent radical C-N cross-coupling of alkyl halides with sulfoximines (as ammonia surrogates) under mild conditions by employing a chiral anionic N,N,N-ligand with a long spreading side arm. An array of α,α-disubstituted amino acid derivatives were obtained with good efficiency and enantioselectivity. The synthetic utility of the strategy has been showcased by the elaboration of the coupling products into different chiral α-fully substituted amine building blocks.

A Counterion/Ligand-Tuned Chemo- and Enantioselective Copper-Catalyzed Intermolecular Radical 1,2-Carboamination of Alkenes.

The copper-catalyzed enantioselective intermolecular radical 1,2-carboamination of alkenes with readily accessible alkyl halides is an appealing strategy for producing chiral amine scaffolds. The challenge arises from the easily occurring atom transfer radical addition between alkyl halides and alkenes and the issue of enantiocontrol. We herein describe a radical alkene 1,2-carboamination with sulfoximines in a highly chemo- and enantioselective manner. The key to the success of this process is the conceptual design of a counterion/highly sterically demanded ligand coeffect to promote the ligand exchange of copper(I) with sulfoximines and forge chiral C-N bonds between alkyl radicals and the chiral copper(II) complex. The reaction covers alkenes bearing distinct electronic properties, such as aryl-, heteroaryl-, carbonyl-, and aminocarbonyl-substituted ones, and various radical precursors, including alkyl chlorides, bromides, iodides, and the CF3 source. Facile transformations deliver many chiral amine building blocks of interest in organic synthesis and related areas.

Substrate composition influences amino acid carbon isotope profiles of fungi: implications for tracing fungal contributions to food webs.

Fungi link detrital resources and metazoan consumers through their role as decomposers. However, fungal contributions to metazoans may be misestimated in amino acid isotope studies because fungi are capable of both synthesizing amino acids (AAs) de novo and absorbing AAs from their environment. While fungi cultured in AA-free media have been used to represent fungi in studies of natural environments, fungi likely gain energetic benefits by taking up substrate AAs directly in situ. Consequently, fungi cultured on AA-free media may not be representative of the true variability of natural fungal δ13 CAA profiles. Therefore, the objective of this experiment was to determine the effect of substrate AA availability on yeast δ13 CAA profiles. We found that yeasts cultured in media of relatively higher AA content had different δ13 CAA profiles than yeasts grown in AA-free media, in part because yeasts utilized two essential AAs (Leu and Val) directly from media substrates when available in sufficient amounts. Furthermore, these differences among yeast δ13 CAA profiles remained after normalization of δ13 CAA values. We recommend further characterization of the variation in fungal δ13 CAA profiles and the incorporation of this potential variability into interpretations of basal resource use by metazoans.

Placensin is a glucogenic hormone secreted by human placenta.

FBN1 encodes asprosin, a glucogenic hormone, following furin cleavage of the C-terminus of profibrillin 1. Based on evolutionary conservation between FBN1 and FBN2, together with conserved furin cleavage sites, we identified a peptide hormone placensin encoded by FBN2 based on its high expression in trophoblasts of human placenta. In primary and immortalized murine hepatocytes, placensin stimulates cAMP production, protein kinase A (PKA) activity, and glucose secretion, accompanied by increased expression of gluconeogenesis enzymes. In situ perfusion of liver and in vivo injection with placensin also stimulate glucose secretion. Placensin is secreted by immortalized human trophoblastic HTR-8/SVneo cells, whereas placensin treatment stimulates cAMP-PKA signaling in these cells, accompanied by increases in MMP9 transcripts and activities, thereby promoting cell invasion. In pregnant women, levels of serum placensin increase in a stage-dependent manner. During third trimester, serum placensin levels of patients with gestational diabetes mellitus are increased to a bigger extent compared to healthy pregnant women. Thus, placensin represents a placenta-derived hormone, capable of stimulating glucose secretion and trophoblast invasion.

Cellular senescence: a promising therapeutic target in colorectal cancer.

Colorectal cancer is one of the most malignant cancers worldwide, and efforts have been made to elucidate the mechanism of colorectal carcinogenesis. Cellular senescence is a physiological process in cell life, but it is also found in cancer initiation and progression. Lines of evidence show that senescence may influence the development and progression of colorectal carcinogenesis. Here, the authors review the characteristics of senescence and the recent findings of a relationship between senescence and colorectal cancer.

Cancer is a leading cause of death worldwide; out of the top ten most common cancers in 2020, the incidence and mortality rate of colorectal cancer (CRC) ranked third and second, respectively. Based on statistics, it was estimated that more than 1.9 million CRC cases occurred in 2020. In terms of CRC, a prominent risk factor is age, and studies suggest that the aging process plays a role in CRC initiation and progression. This review discusses how aging contributes to CRC carcinogenesis and summarizes recent findings on potential therapeutics.