Genetic improvement of phosphate-limited photosynthesis for high yield in rice.

Low phosphate (Pi) availability decreases photosynthesis, with phosphate limitation of photosynthesis occurring particularly during grain filling of cereal crops; however, effective genetic solutions remain to be established. We previously discovered that rice phosphate transporter OsPHO1;2 controls seed (sink) development through Pi reallocation during grain filling. Here, we find that OsPHO1;2 regulates Pi homeostasis and thus photosynthesis in leaves (source). Loss-of-function of OsPHO1;2 decreased Pi levels in leaves, leading to decreased photosynthetic electron transport activity, CO2 assimilation rate, and early occurrence of phosphate-limited photosynthesis. Interestingly, ectopic expression of OsPHO1;2 greatly increased Pi availability, and thereby, increased photosynthetic rate in leaves during grain filling, contributing to increased yield. This was supported by the effect of foliar Pi application. Moreover, analysis of core rice germplasm resources revealed that higher OsPHO1;2 expression was associated with enhanced photosynthesis and yield potential compared to those with lower expression. These findings reveal that phosphate-limitation of photosynthesis can be relieved via a genetic approach, and the OsPHO1;2 gene can be employed to reinforce crop breeding strategies for achieving higher photosynthetic efficiency.

Liposomal STAT3-Degrading PROTAC Prodrugs Promote Anti-Hepatocellular Carcinoma Immunity via Chemically Reprogramming Cancer Stem Cells.

Cancer stem cells (CSCs) with hyperactivated signal transducer and activator of transcription 3 (STAT3) are a major driver of hepatocellular carcinoma (HCC). Herein, we report a nanointegrative proteolysis-targeting chimera (PROTAC)-based STAT3 degradation strategy that enables efficient chemical reprogramming of HCC-associated CSCs, which potently inhibits CSC growth while evoking anti-HCC immune responses. The PROTAC prodrug was synthesized by conjugating the STAT3 binding domain (inS3) with a thioketal-caged E3 ligase ligand (VL-TK) via an oligo(ethylene glycol) linker (OEG) with tuned length and flexibility and encapsulating it in cRGD-modified cationic liposomes for CSC-targeted delivery while facilitating their lysosomal escape. The PROTAC prodrugs were activated by the upregulated ROS levels in CSCs and efficiently degraded STAT3 for chemical reprogramming, which would not only impair their stemness features but also remodel the immunosuppressive TME into an immunosupportive state to boost anti-HCC immunity. This strategy provides an approach for improving HCC treatment in clinics.

Regulatory NADH dehydrogenase-like complex optimizes C4 photosynthetic carbon flow and cellular redox in maize.

C4 plants typically operate a CO2 concentration mechanism from mesophyll (M) cells into bundle sheath (BS) cells. NADH dehydrogenase-like (NDH) complex is enriched in the BS cells of many NADP-malic enzyme (ME) type C4 plants and is more abundant in C4 than in C3 plants, but to what extent it is involved in the CO2 concentration mechanism remains to be experimentally investigated. We created maize and rice mutants deficient in NDH function and then used a combination of transcriptomic, proteomic, and metabolomic approaches for comparative analysis. Considerable decreases in growth, photosynthetic activities, and levels of key photosynthetic proteins were observed in maize but not rice mutants. However, transcript abundance for many cyclic electron transport (CET) and Calvin-Benson cycle components, as well as BS-specific C4 enzymes, was increased in maize mutants. Metabolite analysis of the maize ndh mutants revealed an increased NADPH : NADP ratio, as well as malate, ribulose 1,5-bisphosphate (RuBP), fructose 1,6-bisphosphate (FBP), and photorespiration intermediates. We suggest that by optimizing NADPH and malate levels and adjusting NADP-ME activity, NDH functions to balance metabolic and redox states in the BS cells of maize (in addition to ATP supply), coordinating photosynthetic transcript abundance and protein content, thus directly regulating the carbon flow in the two-celled C4 system of maize.

A wild melon reference genome provides novel insights into the domestication of a key gene responsible for melon fruit acidity.

KEY MESSAGE: A wild melon reference genome elucidates the genomic basis of fruit acidity domestication. Structural variants (SVs) have been reported to impose major effects on agronomic traits, representing a significant contributor to crop domestication. However, the landscape of SVs between wild and cultivated melons is elusive and how SVs have contributed to melon domestication remains largely unexplored. Here, we report a 379-Mb chromosome-scale genome of a wild progenitor melon accession "P84", with a contig N50 of 14.9 Mb. Genome comparison identifies 10,589 SVs between P84 and four cultivated melons with 6937 not characterized in previously analysis of 25 melon genome sequences. Furthermore, the population-scale genotyping of these SVs was determined in 1175 accessions, and 18 GWAS signals including fruit acidity, fruit length, fruit weight, fruit color and sex determination were detected. Based on these genotyped SVs, we identified 3317 highly diverged SVs between wild and cultivated melons, which could be the potential SVs associated with domestication-related traits. Furthermore, we identify novel SVs affecting fruit acidity and proposed the diverged evolutionary trajectories of CmPH, a key regulator of melon fruit acidity, during domestication and selection of different populations. These results will offer valuable resources for genomic studies and genetic improvement in melon.

No association between oral contraceptive exposure and subsequent MS: A population-based nested case-control study in primary care.

BACKGROUND: Conflicting data exist around oral contraceptive exposure and subsequent multiple sclerosis (MS). OBJECTIVE: To use routinely collected primary healthcare data to explore the potential association between oral contraceptive exposure and subsequent MS in females at population level. METHODS: We performed a nested case-control study using electronic primary care data, with complete electronic ascertainment from 1990. Logistic regression was used to evaluate associations between contraceptive exposure and MS, without and with adjusting for age, ethnicity and deprivation. RESULTS: A total of 4455 females were included: 891 cases and 3564 controls. No association was seen between oral contraceptive exposure and subsequent MS, or between any contraceptive, combined oral contraceptive pill (COCP) or progesterone-only pill (POP) use 0-2, 2-5 or >5 years prior to MS. Conclusions: In the largest population-based study to date, we find no evidence of an association between oral contraceptive exposure and subsequent MS diagnosis.

Recycling Organic Dyes within the Metal-Organic Framework for Photothermal Conversion.

The pursuit of a straightforward method to recycle organic dyes from effluents and repurpose them into valuable materials represents a highly sought-after yet huge challenge within the realms of chemistry, environment, and materials science. In this context, we employ a host-guest strategy that leverages the recycling of the rhodamine B molecule within the porous structure of a metal-organic framework to facilitate photothermal conversion. This achievement is realized through the electrostatic interaction, which then gives rise to remarkable selectivity and unparalleled uptake capacity for the cationic rhodamine B molecule. Capitalizing on this approach, the application of a columnar device and membrane technology for efficiently trapping rhodamine B molecules becomes feasible. On account of the aggregation effect resulting from the confined pore structure of the host matrix, the fluorescence emission of the encapsulated RhB molecules is significantly reduced, which consequently enhances the photothermal performance of the hybrid material through nonradiative transition. Moreover, the photothermal conversion achieved showcases a myriad of high-performance applications, including bacterial inhibition against Escherichia coli and seawater desalination.

Delays in Multiple Sclerosis diagnosis (DIMES): protocol for a multicentre, observational study of multiple sclerosis diagnostic pathways in the United Kingdom and Republic of Ireland.

BACKGROUND: Multiple sclerosis (MS) is a leading cause of non-traumatic disability in young adults. Accumulating evidence indicates early diagnosis and early treatment improves long-term outcomes. However, the MS diagnostic pathway is increasingly complex, and delays may occur at several stages. Factors causing delays remain understudied. We aim to quantify the time taken for MS to be diagnosed, and characterise the diagnostic pathway and initial care provided, in the United Kingdom (UK) and Republic of Ireland (ROI). METHODS: Delays In MultiplE Sclerosis diagnosis (DIMES) in the UK and ROI is a multicentre, observational, retrospective study that will be conducted via the Neurology and Neurosurgery Interest Group (NANSIG) collaborative network. Any hospital in the UK and ROI providing an MS diagnostic service is eligible to participate. Data on consecutive individuals newly diagnosed with MS between 1st July 2022 and 31st December 2022 will be collected. The primary outcomes are 1) time from symptoms/signs prompting referral to neurology, to MS diagnosis; and 2) time from referral to neurology for suspected MS, to MS diagnosis. Secondary outcomes include: MS symptoms, referring specialties, investigations performed, neurology appointments, functional status, use of disease modifying treatments, and support at diagnosis including physical activity, and follow up. Demographic characteristics of people newly diagnosed with MS will be summarised, adherence to quality standards summarised as percentages, and time-to-event variables presented with survival curves. Multivariable models will be used to investigate the association of demographic and clinical factors with time to MS diagnosis, as defined in our primary outcomes. DISCUSSION: DIMES aims to be the largest multicentre study of the MS diagnostic pathway in the UK and ROI. The proposed data collection provides insights that cannot be provided from contemporary registries, and the findings will inform approaches to MS services nationally in the future.

Facile fabrication of Ti4+-immobilized magnetic nanoparticles by phase-transitioned lysozyme nanofilms for enrichment of phosphopeptides.

In this study, titanium (IV)-immobilized magnetic nanoparticles (Ti4+-PTL-MNPs) were firstly synthesized via a one-step aqueous self-assembly of lysozyme nanofilms for efficient phosphopeptide enrichment. Under physiological conditions, lysozymes readily self-organized into phase-transitioned lysozyme (PTL) nanofilms on Fe3O4@SiO2 and Fe3O4@C MNP surfaces with abundant functional groups, including -NH2, -COOH, -OH, and -SH, which can be used as multiple linkers to efficiently chelate Ti4+. The obtained Ti4+-PTL-MNPs possessed high sensitivity of 0.01 fmol µL-1 and remarkable selectivity even at a mass ratio of ß-casein to BSA as low as 1:400 for phosphopeptide enrichment. Furthermore, the synthesized Ti4+-PTL-MNPs can also selectively identify low-abundance phosphopeptides from extremely complicated human serum samples and their rapid separation, good reproducibility, and excellent recovery were also proven. This one-step self-assembly of PTL nanofilms facilitated the facile and efficient surface functionalization of various nanoparticles for proteomes/peptidomes.

Synthesis of Fe-N doped porous carbon/silicate composites regulated by minerals in coal gasification fine slag for synergistic electrocatalytic treatment of phenolic wastewater.

Coal gasification fine slag (CGFS), as a difficult-to-dispose solid waste in the coal chemical industry, consists of minerals and residual carbon. Due to the aggregate structure of minerals blocking pores and encapsulating active substances, the high-value utilization of CGFS still remains a challenge. Based on the intrinsic characteristics of CGFS, this study synthesized Fe-N doped porous carbon/silicate composites (Fe-NC) by alkali activation and pyrolysis for electrocatalytic degradation of phenolic wastewater. Meanwhile, minerals were utilized to regulate the surface chemical and pore structure, turning their disadvantages into advantages, which caused a sharp increase in m-cresol mineralization. The positive effect of minerals on composite properties was investigated by characterization techniques, electrochemical analyses and density functional theory (DFT) calculations. It was found that the mesoporous structure of the mineral-regulated composites was further developed, with more carbon defects and reactive substances on its surface. Most importantly, silicate mediated iron conversion through strong interaction with H2O2, high work function gradient with electroactive iron, and excellent superoxide radical (•O2-) production capacity. It effectively improved the reversibility and kinetics of the entire electrocatalytic reaction. Within the Fe-NC311 electrocatalytic system, the m-cresol removal rate reached 99.55 ± 1.24%, surpassing most reported Fe-N-doped electrocatalysts. In addition, the adsorption and electrooxidation experiment confirmed that the synergistic effect of Fe-N doped porous carbon and silicate simultaneously promoted the capture of pollutants and the transformation of electroactive molecules, and hence effectively shortened the diffusion path of short-lived radicals, which was further supported by molecular dynamics simulation. Therefore, this research provides new insights into the problem of mineral limitations and opens an innovative approach for CGFS recycling and environmental remediation.

Bifunctional MNPs@UIO-66-Arg core-shell-satellite nanocomposites for enrichment of phosphopeptides.

A facile and mild method based on self-assembled lysozyme (LYZ) to fabricate bifunctional MNPs@UIO-66-Arg core-shell-satellite nanocomposites (CSSNCs) is reported for the high-efficiency enrichment of phosphopeptides. Under physiological conditions, LYZ rapidly self-assembled into a robust coating on Fe3O4@SiO2 magnetic nanoparticles (MNPs) with abundant surface functional groups, which effectively mediate heterogeneous nucleation and growth of UIO-66 nanocrystals. Well-defined MNPs@UIO-66 CSSNCs with stacked pores, showing high specific surface area (333.65 m2 g- 1) and low mass transfer resistance, were successfully fabricated by fine-tuning of the reaction conditions including reaction time and acetic acid content. Furthermore, the UIO-66 shells were further modified with arginine to obtain bifunctional MNPs@UIO-66-Arg CSSNCs. Thanks to the unique morphology and synergistic effect of Zr-O clusters and guanidine groups, the bifunctional MNPs@UIO-66-Arg CSSNCs exhibited outstanding enrichment performance for phosphopeptides, delivering a low limit of detection (0.1 fmol), high selectivity (ß-casein/BSA, mass ratio 1:2000), and good capture capacity (120 mg g- 1). The mechanism for phosphopeptides capture may attribute to the hydrogen bonds, electrostatic interactions, and Zr-O-P bonds between phosphate groups in peptides and guanidyl/Zr-O clusters on bifunctional MNPs@UIO-66-Arg CSSNCs. In addition, the small stacking pores on the core-shell-satellite architecture may selectively capture phosphopeptides with low molecular weight, eliminating interference of other large molecular proteins in complex biological samples.