Phytochromes enhance SOS2-mediated PIF1 and PIF3 phosphorylation and degradation to promote Arabidopsis salt tolerance.

Soil salinity is one of the most detrimental abiotic stresses affecting plant survival, and light is a core environmental signal regulating plant growth and responses to abiotic stress. However, how light modulates the plant's response to salt stress remains largely obscure. Here, we show that Arabidopsis (Arabidopsis thaliana) seedlings are more tolerant to salt stress in the light than in the dark, and that the photoreceptors phytochrome A (phyA) and phyB are involved in this tolerance mechanism. We further show that phyA and phyB physically interact with the salt tolerance regulator SALT OVERLY SENSITIVE2 (SOS2) in the cytosol and nucleus, and enhance salt-activated SOS2 kinase activity in the light. Moreover, SOS2 directly interacts with and phosphorylates PHYTOCHROME-INTERACTING FACTORS PIF1 and PIF3 in the nucleus. Accordingly, PIFs act as negative regulators of plant salt tolerance, and SOS2 phosphorylation of PIF1 and PIF3 decreases their stability and relieves their repressive effect on plant salt tolerance in both light and dark conditions. Together, our study demonstrates that photoactivated phyA and phyB promote plant salt tolerance by increasing SOS2-mediated phosphorylation and degradation of PIF1 and PIF3, thus broadening our understanding of how plants adapt to salt stress according to their dynamic light environment.

Long-read sequencing identifies novel structural variations in colorectal cancer.

Structural variations (SVs) are a key type of cancer genomic alterations, contributing to oncogenesis and progression of many cancers, including colorectal cancer (CRC). However, SVs in CRC remain difficult to be reliably detected due to limited SV-detection capacity of the commonly used short-read sequencing. This study investigated the somatic SVs in 21 pairs of CRC samples by Nanopore whole-genome long-read sequencing. 5200 novel somatic SVs from 21 CRC patients (494 SVs / patient) were identified. A 4.9-Mbp long inversion that silences APC expression (confirmed by RNA-seq) and an 11.2-kbp inversion that structurally alters CFTR were identified. Two novel gene fusions that might functionally impact the oncogene RNF38 and the tumor-suppressor SMAD3 were detected. RNF38 fusion possesses metastasis-promoting ability confirmed by in vitro migration and invasion assay, and in vivo metastasis experiments. This work highlighted the various applications of long-read sequencing in cancer genome analysis, and shed new light on how somatic SVs structurally alter critical genes in CRC. The investigation on somatic SVs via nanopore sequencing revealed the potential of this genomic approach in facilitating precise diagnosis and personalized treatment of CRC.

Mechanisms Underlying the Recruitment of Inhibitory Interneurons in Fictive Swimming in Developing Xenopus laevis Tadpoles.

Developing spinal circuits generate patterned motor outputs while many neurons with high membrane resistances are still maturing. In the spinal cord of hatchling frog tadpoles of unknown sex, we found that the firing reliability in swimming of inhibitory interneurons with commissural and ipsilateral ascending axons was negatively correlated with their cellular membrane resistance. Further analyses showed that neurons with higher resistances had outward rectifying properties, low firing thresholds, and little delay in firing evoked by current injections. Input synaptic currents these neurons received during swimming, either compound, unitary current amplitudes, or unitary synaptic current numbers, were scaled with their membrane resistances, but their own synaptic outputs were correlated with membrane resistances of their postsynaptic partners. Analyses of neuronal dendritic and axonal lengths and their activities in swimming and cellular input resistances did not reveal a clear correlation pattern. Incorporating these electrical and synaptic properties into a computer swimming model produced robust swimming rhythms, whereas randomizing input synaptic strengths led to the breakdown of swimming rhythms, coupled with less synchronized spiking in the inhibitory interneurons. We conclude that the recruitment of these developing interneurons in swimming can be predicted by cellular input resistances, but the order is opposite to the motor-strength-based recruitment scheme depicted by Henneman's size principle. This form of recruitment/integration order in development before the emergence of refined motor control is progressive potentially with neuronal acquisition of mature electrical and synaptic properties, among which the scaling of input synaptic strengths with cellular input resistance plays a critical role.SIGNIFICANCE STATEMENT The mechanisms on how interneurons are recruited to participate in circuit function in developing neuronal systems are rarely investigated. In 2-d-old frog tadpole spinal cord, we found the recruitment of inhibitory interneurons in swimming is inversely correlated with cellular input resistances, opposite to the motor-strength-based recruitment order depicted by Henneman's size principle. Further analyses showed the amplitude of synaptic inputs that neurons received during swimming was inversely correlated with cellular input resistances. Randomizing/reversing the relation between input synaptic strengths and membrane resistances in modeling broke down swimming rhythms. Therefore, the recruitment or integration of these interneurons is conditional on the acquisition of several electrical and synaptic properties including the scaling of input synaptic strengths with cellular input resistances.

Protein O-GlcNAcylation impairment caused by N-acetylglucosamine phosphate mutase deficiency leads to growth variations in Arabidopsis thaliana.

As an essential enzyme in the uridine diphosphate (UDP)-GlcNAc biosynthesis pathway, the significant role of N-acetylglucosamine phosphate mutase (AGM) remains unknown in plants. In the present study, a functional plant AGM (AtAGM) was identified from Arabidopsis thaliana. AtAGM catalyzes the isomerization of GlcNAc-1-P and GlcNAc-6-P, and has broad catalytic activity on different phosphohexoses. UDP-GlcNAc contents were significantly decreased in AtAGM T-DNA insertional mutants, which caused temperature-dependent growth defects in seedlings and vigorous growth in adult plants. Further analysis revealed that protein O-GlcNAcylation but not N-glycosylation was dramatically impaired in Atagm mutants due to UDP-GlcNAc shortage. Combined with the results from O-GlcNAcylation or N-glycosylation deficient mutants, and O-GlcNAcase inhibitor all suggested that protein O-GlcNAcylation impairment mainly leads to the phenotypic variations of Atagm plants. In conclusion, based on the essential role in UDP-GlcNAc biosynthesis, AtAGM is important for plant growth mainly via protein O-GlcNAcylation-level regulation.

Roles of leukemia inhibitory factor receptor in cancer.

Leukemia inhibitory factor receptor (LIFR), in complex with glycoprotein 130 (gp130) as the receptor for leukemia inhibitory factor (LIF), can bind to a variety of cytokines and subsequently activate a variety of signaling pathways, including Janus kinase/signal transducer and activator of transcription 3. LIF, the most multifunctional cytokines of the interleukin-6 family acts as both a growth factor and a growth inhibitor in different types of tumors. LIF/LIFR signaling regulates a broad array of tumor-related processes including proliferation, apoptosis, migration, invasion. However, due to the activation of different signaling pathways, opposite regulatory effects are observed in certain tumor cells. Therefore, the role of LIFR in human cancers varies across different tumor and tissue, despite their recognized value in tumor treatment and prognosis observation is affirmed. Given its aberrant expression in numerous tumor cells and crucial regulatory function in tumorigenesis and progression, LIFR is considered as a promising targeted therapeutic agent. This review provides an overview of LIFR's initiating signaling pathway function as a cytokine receptor and summarize the current literature on the role of LIFR in cancer and its possible use in therapy.

USP3: Key deubiquitylation enzyme in human diseases.

Ubiquitination and deubiquitylation are pivotal posttranslational modifications essential for regulating cellular protein homeostasis and are implicated in the development of human diseases. Ubiquitin-specific protease 3 (USP3), a member of the ubiquitin-specific protease family, serves as a key deubiquitylation enzyme, playing a critical role in diverse cellular processes including the DNA damage response, cell cycle regulation, carcinogenesis, tumor cell proliferation, migration, and invasion. Despite notable research efforts, our current understanding of the intricate and context-dependent regulatory networks governing USP3 remains incomplete. This review aims to comprehensively synthesize existing published works on USP3, elucidating its multifaceted roles, functions, and regulatory mechanisms, while offering insights for future investigations. By delving into the complexities of USP3, this review strives to provide a foundation for a more nuanced understanding of its specific roles in various cellular processes. Furthermore, the exploration of USP3's regulatory networks may uncover novel therapeutic strategies targeting this enzyme in diverse human diseases, thereby holding promising clinical implications. Overall, an in-depth comprehension of USP3's functions and regulatory pathways is crucial for advancing our knowledge and developing targeted therapeutic approaches for human diseases.

Guselkumab in Patients With Moderately to Severely Active Ulcerative Colitis: QUASAR Phase 2b Induction Study.

BACKGROUND & AIMS: The QUASAR Phase 2b Induction Study evaluated the efficacy and safety of guselkumab, an interleukin-23p19 subunit antagonist, in patients with moderately to severely active ulcerative colitis (UC) with prior inadequate response and/or intolerance to corticosteroids, immunosuppressants, and/or advanced therapy. METHODS: In this double-blind, placebo-controlled, dose-ranging, induction study, patients were randomized (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0/4/8. The primary endpoint was clinical response (compared with baseline, modified Mayo score decrease ≥30% and ≥2 points, rectal bleeding subscore ≥1-point decrease or subscore of 0/1) at week 12. Guselkumab and placebo week-12 clinical nonresponders received subcutaneous or intravenous guselkumab 200 mg, respectively, at weeks 12/16/20 (uncontrolled study period). RESULTS: The primary analysis population included patients with baseline modified Mayo scores ≥5 and ≤9 (intravenous guselkumab 200 mg, n = 101; 400 mg, n = 107; placebo, n = 105). Week-12 clinical response percentage was greater with guselkumab 200 mg (61.4%) and 400 mg (60.7%) vs placebo (27.6%; both P < .001). Greater proportions of guselkumab-treated vs placebo-treated patients achieved all major secondary endpoints (clinical remission, symptomatic remission, endoscopic improvement, histo-endoscopic mucosal improvement, and endoscopic normalization) at week 12. Among guselkumab week-12 clinical nonresponders, 54.3% and 50.0% of patients in the 200- and 400-mg groups, respectively, achieved clinical response at week 24. Safety was similar among guselkumab and placebo groups. CONCLUSIONS: Guselkumab intravenous induction was effective vs placebo in patients with moderately to severely active UC. Guselkumab was safe, and efficacy and safety were similar between guselkumab dose groups. CLINICALTRIALS: gov number: NCT04033445.

Efficacy and Safety of Ustekinumab for Ulcerative Colitis Through 4 Years: Final Results of the UNIFI Long-Term Maintenance Study.

INTRODUCTION: Ulcerative colitis (UC) is a chronic condition that may require long-term treatment. We report the final efficacy and safety results of the UNIFI long-term extension study of ustekinumab in patients with UC through 4 years. METHODS: Ustekinumab induction responders who completed 44 weeks of maintenance treatment and agreed to enter the long-term extension continued their subcutaneous maintenance therapy (90 mg ustekinumab every 8 or 12 weeks [q8w or q12w] or placebo). Starting at week 56, randomized patients could receive dose adjustment to 90 mg q8w. Symptoms and adverse events were assessed through the study; endoscopic assessment was conducted at week 200. RESULTS: Of the 348 patients randomized to subcutaneous ustekinumab at maintenance baseline (q8w and q12w combined), 55.2% were in symptomatic remission at week 200. A greater proportion of biologic-naive patients (67.2% [117/174]) were in symptomatic remission than those with a history of biologic failure (41.6% [67/161]). Among patients in symptomatic remission at week 200, 96.4% were corticosteroid-free. Of the 171 patients with endoscopic evaluation at week 200, 81.6% (71/87) in the q12w group and 79.8% (67/84) in the q8w group had endoscopic improvement. From weeks 156 to the final safety visit (up to week 220), no deaths, major adverse cardiovascular events, or tuberculosis occurred in patients receiving ustekinumab. Nasopharyngitis, UC worsening, and upper respiratory tract infections were the most frequently reported adverse events. DISCUSSION: The long-term efficacy of ustekinumab maintenance in patients with UC was confirmed through 4 years. No new safety signals were observed. ClinicalTrials.gov number NCT02407236.

p110CUX1 promotes acute myeloid leukemia progression via regulating pyridoxal phosphatase expression and activating PI3K/AKT/mTOR signaling pathway.

As an evolutionarily conserved transcription factor, Cut-like homeobox 1 (CUX1) plays crucial roles in embryonic and nervous system development, cell differentiation, and DNA damage repair. One of its major isoforms, p110CUX1, exhibits stable DNA binding capabilities and contributes to the regulation of cell cycle progression, proliferation, migration, and invasion. While p110CUX1 has been implicated in the progression of various malignant tumors, its involvement in acute myeloid leukemia (AML) remains uncertain. This study aims to elucidate the role of p110CUX1 in AML. Our findings reveal heightened expression levels of both p110CUX1 and pyridoxal phosphatase (PDXP) in AML cell lines. Overexpression of p110CUX1 promotes AML cell proliferation while inhibiting apoptosis and differentiation, whereas knockdown of PDXP yields contrasting effects. Mechanistically, p110CUX1 appears to facilitate AML development by upregulating PDXP expression and activating the PI3K/AKT/mTOR signaling pathway. Animal experimental corroborate the pro-AML effect of p110CUX1. These results provide experimental evidence supporting the involvement of the p110CUX1-PDXP-PI3K/AKT/mTOR axis in AML progression. Hence, targeting p110CUX1 may hold promise as a therapeutic strategy for AML.

Causal inference between pernicious anemia and cancers: a bidirectional two-sample mendelian randomization analysis.

BACKGROUND: Observational study investigated the association between pernicious anemia (PA) and cancers. However, with the exception of gastric cancer, the results are mostly contradictory. The purpose of this study was to investigate the potential causal relationship between PA and cancers through bidirectional two-sample Mendelian randomized (MR) analysis. METHODS: The European sample FinnGen project provided the genetic summary data for PA and 20 site-specific cancers. This bidirectional two-sample MR design mainly used the inverse variance weighting (IVW) method to evaluate the causal relationship between PA and cancer risk. Benjamini-Hochberg correction was performed to reduce the bias caused by multiple tests. RESULTS: Our study shows that there was a causal relationship between PA and gastric cancer, prostate cancer, testicular cancer and malignant melanoma of skin, and there was a reverse causal relationship between prostate cancer or gastric cancer and PA (P < 0.05). After Benjamini-Hochberg correction test, there was still a causal correlation between PA and gastric or prostate cancer (P' < 0.05), while there was only an implied causal association between PA and testicular cancer and malignant melanoma of skin (P'> 0.05). There was still a reverse causal relationship between gastric cancer and PA (P'< 0.05), while prostate cancer shows an implied reverse causal relationship(P'> 0.05). In addition, MR-Egger and MR-PRESSO tests showed no significant horizontal pleiotropy. CONCLUSIONS: PA may be genetically associated with testicular cancer, prostate cancer, gastric cancer, and malignant melanoma of skin.

Preoperative Subtyping of WHO Grade 1 Meningiomas Using a Single-Shot Ultrafast MR T2 Mapping.

BACKGROUND: Meningioma subtype is crucial in treatment planning and prognosis delineation, for grade 1 meningiomas. T2 relaxometry could provide detailed microscopic information but is often limited by long scanning times. PURPOSE: To investigate the potential of T2 maps derived from multiple overlapping-echo detachment imaging (MOLED) for predicting meningioma subtypes and Ki-67 index, and to compare the diagnostic efficiency of two different region-of-interest (ROI) placements (whole-tumor and contrast-enhanced, respectively). STUDY TYPE: Prospective. PHANTOM/SUBJECTS: A phantom containing 11 tubes of MnCl2 at different concentrations, eight healthy volunteers, and 75 patients with grade 1 meningioma. FIELD STRENGTH/SEQUENCE: 3 T scanner. MOLED, T2-weighted spin-echo sequence, T2-dark-fluid sequence, and postcontrast T1-weighted gradient echo sequence. ASSESSMENT: Two ROIs were delineated: the whole-tumor area (ROI1) and contrast-enhanced area (ROI2). Histogram parameters were extracted from T2 maps. Meningioma subtypes and Ki-67 index were reviewed by a neuropathologist according to the 2021 classification criteria. STATISTICAL TESTS: Linear regression, Bland-Altman analysis, Pearson's correlation analysis, independent t test, Mann-Whitney U test, Kruskal-Wallis test with Bonferroni correction, and multivariate logistic regression analysis with the P-value significance level of 0.05. RESULTS: The MOLED T2 sequence demonstrated excellent accuracy for phantoms and volunteers (Meandiff = -1.29%, SDdiff = 1.25% and Meandiff = 0.36%, SDdiff = 2.70%, respectively), and good repeatability for volunteers (average coefficient of variance = 1.13%; intraclass correlation coefficient = 0.877). For both ROI1 and ROI2, T2 variance had the highest area under the curves (area under the ROC curve = 0.768 and 0.761, respectively) for meningioma subtyping. There was no significant difference between the two ROIs (P = 0.875). Significant correlations were observed between T2 parameters and Ki-67 index (r = 0.237-0.374). DATA CONCLUSION: MOLED T2 maps can effectively differentiate between meningothelial, fibrous, and transitional meningiomas. Moreover, T2 histogram parameters were significantly correlated with the Ki-67 index. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY: Stage 2.

A computational and experimental study of cis-trans isomeric pesticides based on collision-induced dissociation of high-resolution mass spectrometry.

RATIONALE: Pesticide isomers are widely available in agricultural production and may vary widely in biological activity, potency, and toxicity. Chromatographic and mass spectrometric analysis of pesticide isomers is challenging due to structural similarities. METHODS: Based on liquid chromatography time-of-flight mass spectrometry, identification of cis-trans isomeric pesticides was achieved through retention time, characteristic fragment ions, and relative abundance ratio. Furthermore, theoretical and basic research has been conducted on the differences in characteristic fragment ions and their relative abundance ratios of cis-trans isomers. On the one hand, the cleavage pathways of six cis-trans isomers were elucidated through collision-induced dissociation to explain different fragment ions of the isomers. On the other hand, for those with the same fragment ions but different abundance ratios, energy-resolved mass spectrometry combined with computational chemical density functional theory in terms of kinetics, thermodynamics, and bond lengths was employed to explain the reasons for the differences in characteristic fragment ions and their abundance ratios. RESULTS: A high-resolution mass spectrometry method was developed for the separation and analysis of cis-trans isomers of pesticides in traditional Chinese medicine Radix Codonopsis, and six pesticide isomers were distinguished by retention time, product ions, and relative abundance ratios. The limits of quantification of the six pesticides were up to 10 µg/kg, and the linear ranges of them were 10-200 µg/kg, with coefficients of determination (R2) > 0.99, which demonstrated the good linearity of the six pesticides. The recoveries of the pesticides at spiked concentrations of 10, 20, and 100 µg/kg reached 70-120% with relative standard deviations ≤20%. CONCLUSIONS: It was demonstrated that the application of the method was well suited for accurate qualitative and quantitative analysis for isomers with different structures, which could avoid false-negative results caused by ignoring other isomers effectively.

Qualitative and Psychometric Evaluation of 29-Item Patient-Reported Outcomes Measurement Information System® to Assess General Health-Related Quality of Life in Patients With Moderately to Severely Active Inflammatory Bowel Disease.

OBJECTIVES: To evaluate content validity and psychometric properties of the 29-item Patient-Reported Outcomes Measurement Information System (PROMIS-29) to determine its suitability in inflammatory bowel disease (IBD) clinical trials. METHODS: Content validity of PROMIS-29 was evaluated using qualitative interviews, including concept elicitation and cognitive debriefing, among patients living with Crohn's disease (Crohn's disease n = 20) or ulcerative colitis (UC, n = 19). PROMIS-29 validity, reliability, and responsiveness were assessed using data from phase II clinical trials of Crohn's disease (N = 360) and UC (N = 518). RESULTS: Common (≥74%) symptoms reported in qualitative interviews were increased stool frequency, fatigue, abdominal pain/cramping, blood/mucus in stool, bowel urgency, and diarrhea. Disease impact aligned with PROMIS-29 content (depression, anxiety, physical function, pain interference, fatigue, sleep disturbance, and ability to participate in social roles/activities). Cognitive debriefing indicated that PROMIS-29 instructions were easily understood, items were relevant, and the recall period was appropriate. Psychometric evaluations demonstrated that PROMIS-29 scores indicating worse symptoms/functioning were associated with lower health-related quality of life and greater disease activity and severity. PROMIS-29 domain scores correlated (rs ≥ 0.40) with IBD Questionnaire domains and EuroQol-5-Dimension-5-Level dimensions measuring similar concepts. Test-retest reliability among patients with stable disease was moderate-to-excellent (0.64-0.94) for nearly all domains in all studies. PROMIS-29 was responsive to change in disease status from baseline to week 12. Thresholds for clinically meaningful improvement ranged from ≥3 to ≥8, depending on domain. CONCLUSIONS: PROMIS-29 is valid, reliable, and responsive for assessing general health-related quality of life and treatment response in IBD clinical trials.

Molecular-Level Insights into the Relationship between Volatility of Organic Aerosol Constituents and PM2.5 Air Pollution Levels: A Study with Ultrahigh-Resolution Mass Spectrometry.

Volatility of organic aerosols (OAs) significantly influences new particle formation and the occurrence of particulate air pollution. However, the relationship between the volatility of OA and the level of particulate air pollution (i.e., particulate matter concentration) is not well understood. In this study, we compared the chemical composition (identified by an ultrahigh-resolution Orbitrap mass spectrometer) and volatility (estimated based on a predeveloped parametrization method) of OAs in urban PM2.5 (particulate matter with aerodynamic diameter ≤ 2.5 µm) samples from seven German and Chinese cities, where the PM2.5 concentration ranged from a light (14 µg m-3) to heavy (319 µg m-3) pollution level. A large fraction (71-98%) of compounds in PM2.5 samples were attributable to intermediate-volatility organic compounds (IVOCs) and semivolatile organic compounds (SVOCs). The fraction of low-volatility organic compounds (LVOCs) and extremely low-volatility organic compounds (ELVOCs) decreased from clean (28%) to heavily polluted urban regions (2%), while that of IVOCs increased from 34 to 62%. We found that the average peak area-weighted volatility of organic compounds in different cities showed a logarithmic correlation with the average PM2.5 concentration, indicating that the volatility of urban OAs increases with the increase of air pollution level. Our results provide new insights into the relationship between OA volatility and PM pollution levels and deepen the understanding of urban air pollutant evolution.

The lead-free perovskite-based heterojunction C2N/CsGeI3: an exploration for superior visible-light absorption.

Halide perovskites have distinguished themselves among the numerous optoelectronic materials due to their versatile processing technology and exceptional optical response. Unfortunately, their stability and toxicity from heavy metals severely hamper their development, in addition to the challenge of further improving photovoltaic performance. Hence, a lead-free perovskite-based heterojunction, C2N/CsGeI3, is investigated using a hybrid density functional, including electron structures, charge density differences, optical properties and more. The study reveals the presence of a built-in electric field directed from the CsGeI3 to the C2N layer. Moreover, based on the work function, it is confirmed that the electrons are transferred in a Z-scheme mechanism after the CsGeI3 contacts with the C2N layer. Under light irradiation, the construction of the C2N/CsGeI3 heterojunction significantly enhances optical absorption within the range of visible-light wavelengths. Additionally, the impact of interfacial strain on the C2N/CsGeI3 is explored and discussed. These findings not only suggest that the C2N/CsGeI3 heterojunction holds promise for photovoltaic applications but also provide a theoretical insight into lead-free perovskite-based functional materials.

Pursuing sustainable productivity with millions of smallholder farmers.

Sustainably feeding a growing population is a grand challenge, and one that is particularly difficult in regions that are dominated by smallholder farming. Despite local successes, mobilizing vast smallholder communities with science- and evidence-based management practices to simultaneously address production and pollution problems has been infeasible. Here we report the outcome of concerted efforts in engaging millions of Chinese smallholder farmers to adopt enhanced management practices for greater yield and environmental performance. First, we conducted field trials across China's major agroecological zones to develop locally applicable recommendations using a comprehensive decision-support program. Engaging farmers to adopt those recommendations involved the collaboration of a core network of 1,152 researchers with numerous extension agents and agribusiness personnel. From 2005 to 2015, about 20.9 million farmers in 452 counties adopted enhanced management practices in fields with a total of 37.7 million cumulative hectares over the years. Average yields (maize, rice and wheat) increased by 10.8-11.5%, generating a net grain output of 33 million tonnes (Mt). At the same time, application of nitrogen decreased by 14.7-18.1%, saving 1.2 Mt of nitrogen fertilizers. The increased grain output and decreased nitrogen fertilizer use were equivalent to US$12.2 billion. Estimated reactive nitrogen losses averaged 4.5-4.7 kg nitrogen per Megagram (Mg) with the intervention compared to 6.0-6.4 kg nitrogen per Mg without. Greenhouse gas emissions were 328 kg, 812 kg and 434 kg CO2 equivalent per Mg of maize, rice and wheat produced, respectively, compared to 422 kg, 941 kg and 549 kg CO2 equivalent per Mg without the intervention. On the basis of a large-scale survey (8.6 million farmer participants) and scenario analyses, we further demonstrate the potential impacts of implementing the enhanced management practices on China's food security and sustainability outlook.

LN-439A, a novel BAP1 inhibitor, suppresses the growth of basal-like breast cancer by degrading KLF5.

Basal-like breast cancer (BLBC) is the most malignant subtype of breast cancer because of its aggressive clinical behaviour and lack of effective targeted agents. Krüppel-like factor 5 (KLF5) is an oncogenic transcription factor that is highly expressed in BLBC. The deubiquitinase (DUB) BRCA1-associated protein 1 (BAP1) stabilizes KLF5 and promotes BLBC growth and metastasis. Therefore, pharmacological inhibition of the BAP1‒KLF5 axis is an effective therapeutic strategy for BLBC. Here, through screening, we identified a series of tetrahydro-ß-carboline derivatives that effectively reduced the protein expression of KLF5 and exhibited strong antitumour activity. Among the investigated compounds, the lead compound LN-439A presented the strongest antitumour activity and inhibitory effect on KLF5 expression. LN-439A suppressed the proliferation and migration of BLBC cells, induced G2/M arrest, and induced apoptosis. Mechanistically, LN-439A functions as a small molecule catalytic inhibitor of BAP1 by binding to the catalytic pocket of BAP1, leading to the ubiquitination and degradation of KLF5. Consistent with this finding, the overexpression of KLF5 suppressed the antitumour effects of LN-439A. In summary, LN-439A is a promising therapeutic agent for BLBC that functions by targeting the BAP1‒KLF5 axis.

Efficacy and safety of botulinum toxin A in the treatment of female pattern hair loss.

BACKGROUND: Female pattern hair loss (FPHL) is the most prevalent type of alopecia among adult women. Presently, topical minoxidil stands as the sole treatment endorsed by the FDA. Addressing cases of FPHL in individuals who develop contact dermatitis in response to minoxidil can pose a challenge for dermatologists. OBJECTIVE: To assess the efficacy and safety of subcutaneous injections of Botulinum Toxin Type A (BTA) in treating FPHL. METHODS: Enrolled outpatients with FPHL who exhibited an allergic reaction to minoxidil solution. Diagnosis of FPHL was established through clinical examination and trichoscopy. Inclusion criteria involved patients with no prior treatment within the last year and without any comorbidities. BTA, specifically 100 units, was mixed with 2 mL of 0.9% normal saline. Twenty injection target sites, spaced 2-3 cm apart, were symmetrically marked on the hairless area of the scalp. A dosage of five units was intradermally injected at each target site. Representative photographs and dermoscopic images of the scalp were captured before and after 3 months of treatment. RESULTS: A total of 10 FPHL, aged between 26 and 40 years, were included. The average age was 30.3 ± 4.64 years, and all patients had a positive family history of Androgenetic Alopecia. The average duration of the disease was 3.70 ± 1.42 years. According to patients' self-assessment, after 1 month of treatment, 10 FPHL patients reported experiencing moderate to marked improvement in symptoms related to scalp oil secretion. Three months later, dermatological assessments showed that three had mild improvement, six had no change, and one had a worsening condition. No adverse effects were observed. CONCLUSIONS: Our study suggests that the effectiveness of BTA for FPHL is limited to 3 months. However, it can be considered for tentative use after effective communication with patients. The long-term efficacy and safety of BTA in treating FPHL require further observation and study.

Ultraviolet-induced red fluorescence in androgenetic alopecia-indicating alterations in microbial composition.

BACKGROUND: Ultraviolet (UV)-induced fluorescence technology is widely used in dermatology to identify microbial infections. Our clinical observations under an ultraviolet-induced fluorescent dermatoscope (UVFD) showed red fluorescence on the scalps of androgenetic alopecia (AGA) patients. In this study, based on the hypothesis that microbes are induced to emit red fluorescence under UV light, we aimed to explore the microbial disparities between the AGA fluorescent area (AF group) and AGA non-fluorescent area (ANF group). METHODS: Scalp swab samples were collected from 36 AGA patients, including both fluorescent and non-fluorescent areas. The bacterial communities on the scalp were analyzed by 16S rRNA gene sequencing and bioinformatics analysis, as well as through microbial culture methods. RESULTS: Significant variations were observed in microbial evenness, abundance composition, and functional predictions between fluorescent and non-fluorescent areas. Sequencing results highlighted significant differences in Cutibacterium abundance between these areas (34.06% and 21.36%, respectively; p < 0.05). Furthermore, cultured red fluorescent colonies primarily consisted of Cutibacterium spp., Cutibacterium acnes, Staphylococcus epidermidis, and Micrococcus spp. CONCLUSIONS: This is the first study to investigate scalp red fluorescence, highlighting microbial composition variability across different scalp regions. These findings may provide novel insights into the microbiological mechanisms of AGA.

Prevalence and influencing factors of patient delay in stroke patients: a systematic review and meta-analysis.

PURPOSE: Determine the prevalence and influencing factors of patient delay in stroke patients and explore variation in prevalence by country and delayed time. METHODS: PubMed, The Cochrane Library, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), Chinese Biomedical Database (CBM), Weipu database, and Wanfang database were comprehensively searched for observational studies from inception to April, 2023. The pooled prevalence, odds ratio (OR), and 95% confidence intervals (CI) were calculated with Stata 16.0 software. RESULTS: In total, 2721 articles were screened and data from 70 studies involving 85,468 subjects were used in meta-analysis. The pooled prevalence of patient delay in stroke patients was 59% (95% CI, 0.54-0.64). The estimates of pooled prevalence calculated for African, Asian, and European patient delay in stroke patients were 55% (0.29-0.81), 61% (0.56-0.66), and 49% (0.34-0.64).According to the patient delay time, the prevalence of 6 h, 5 h, 4.5 h, 3.5 h, 3 h and 2 h were 54% (0.47-0.61), 73% (0.61-0.86), 60% (0.49-0.71), 81% (0.68-0.93), 52% (0.42-0.62), 63% (0.19-1.07). Distance from the place of onset to the hospital > 10 km [OR=2.49, 95%CI (1.92, 3.24)], having medical insurance [OR = 0.45, 95%CI (0.26,0.80)], lack of stroke-related knowledge [OR = 1.56, 95%CI (1.08,2.26)], education level below junior high school [OR = 1.69, 95%CI (1.22,2.36)], non-emergency medical services (Non-EMS) [OR = 2.10, 95%CI (1.49,2.97)], living in rural areas [OR = 1.54, 95%CI (1.15,2.07)], disturbance of consciousness [OR = 0.60, 95%CI (0.39,0.93)], history of atrial fibrillation [OR = 0.53, 95%CI (0.47,0.59)], age ≥ 65 years [OR = 1.18, 95%CI (1.02,1.37)], National institutes of health stroke scale (NIHSS) ≤ 4 points [OR= 2.26, 95%CI (1.06,4.79)]were factors for patient delay in stroke patients. CONCLUSIONS: The prevalence of patient delay in stroke patients is high, we should pay attention to the influencing factors of patient delay in stroke patients and provide a theoretical basis for shortening the treatment time of stroke patients.