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This phase 1 trial assessed the safety and immunogenicity of an investigational tetanus/diphtheria/acellular pertussis vaccine combined with CpG 1018 adjuvant 1500 μg (Tdap-1018 1500 μg) or 3000 μg (Tdap-1018 3000 μg) in adults and adolescents. In this randomized, active-controlled, multicenter, dose-escalation trial, healthy participants aged 10 to 22 years received 1 dose of Tdap-1018 1500 μg, Tdap-1018 3000 μg, or Boostrix. Geometric mean concentrations (GMCs) and booster response rates (BRRs) for antibodies against pertussis (pertussis toxin, filamentous hemagglutinin, pertactin), tetanus, and diphtheria antigens, and neutralizing antibodies against pertussis toxin were assessed 4 weeks after vaccination. Safety and tolerability were assessed for solicited post-injection reactions within 7 days after vaccination and unsolicited adverse events up to 12 weeks after vaccination. Of 117 enrolled participants, 80 adults (92%) and 30 adolescents (100%) completed the study. Both Tdap-1018 formulations were generally well tolerated, with no vaccine-related serious adverse events. Frequency and severity in post-injection reactions after Tdap-1018 administration were similar to Boostrix except for higher proportions of moderate pain for Tdap-1018. In adults at week 4, ratio of GMCs and BRRs for all antigens in the 3000-μg group were similar to or higher than Boostrix, with significantly higher GMC ratios for anti-pertussis toxin (2.1 [1.5-3.0]) and anti-tetanus (1.8 [1.1-2.9]) and significantly higher BRRs for anti-pertussis toxin (difference [95% CI]: 34.5% [13.4-54.6]), anti-pertactin (19.2% [4.4-38.1]), and anti-tetanus (30.0% [3.6-52.7]) antibodies. For adolescents, in the 3000-μg group, ratio of GMCs and BRRs were similar to or higher than Boostrix for all antigens. Both Tdap-1018 formulations showed acceptable safety and tolerability profiles. Tdap-1018 3000 μg induced similar or higher immune responses than Boostrix. ACTRN12620001177943 (Australian New Zealand Clinical Trials Registry; https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12620001177943p)., Competing Interests: Declaration of competing interest F.X. and O.G. are consultants for Dynavax Technologies Corporation. J.D.C., O.H., and R.S.J. are employees of Dynavax Technologies Corporation and may hold company stock. P.R. has served on pertussis vaccine scientific advisory boards on behalf of his institution for GlaxoSmithKline and Sanofi outside the submitted work. T.N. has served on vaccine scientific advisory boards for GSK, Sanofi, Pfizer, CSL Seqirus, MSD, Moderna, and AstraZeneca, and on clinical trial data and safety monitoring boards for GSK, CSL Seqirus, Statens Serum Institute, SK Bioscience Korea, Zeria Pharmaceuticals, Clover, Novavax, Serum Institute of India, and Moderna. A.M., F.N-F., J.K., A.L., and N.W. report no potential conflicts., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Constipation may be linked to cognitive decline and a higher risk of Alzheimer's disease (AD). We aimed to investigate the association between constipation and positron emission tomography (PET) and blood-based AD biomarkers in older cognitively unimpaired (CU) adults with higher Aβ burden., Methods: Constipation was diagnosed according to Rome IV criteria and the severity of constipation was evaluated by using a validated self-reported questionnaire. The participants underwent the examination of plasma AD biomarkers and 18 F-florbetapir PET and 18 F-MK6240 PET scans; the latter was only performed in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the association between constipation and AD biomarkers., Results: Two cohorts were included in our study. A total of 404 older participants with 126 of whom Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed constipation was associated with plasma t-Tau, p-Tau-181, and neurofilament light chain (NfL) in participants with Aβ-PET (+). Meanwhile, no/mild constipation was associated with lower Aβ-PET standard uptake value ratio. The association between constipation and plasma biomarkers was different in the subgroups stratified by age, sex and APOE ε4 genotype. The above associations were further validated in the validation cohort containing 36 Aβ-PET (+) participants. Importantly, no/mild constipation was associated with less Tau burden evaluated by 18 F-MK6240 PET Braak stages., Conclusion: Our data indicate that no/mild constipation may be associated with lower plasma t-Tau, p-Tau-181, and NfL as well as less Aβ and Tau burden in older CU adults with Aβ deposition. Improving constipation and being away from defecation disorders may help reduce the risk of AD development., (© 2024. The Author(s).)

A STING (stimulator of interferon genes) agonist GSK3996915 under investigation in early discovery for hepatitis B was orally dosed to a mouse model for understanding the parent drug distribution in liver, the target organ. Matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry (IMS) was used to quantify the distribution of GSK3996915 in liver collected from mice administered a single oral dose at 90 mg/kg. GSK3996915 was detected with a zonal distribution localized in the portal triad and highly concentrated in the main bile ducts, indicating clearance through biliary excretion. High spatial resolution imaging showed the distribution of the parent drug localized to the cellular populations in the sinusoids, including the Kupffer cells. Additionally, a series of drug-related metabolites were observed to be localized in the central zones of the liver. These results exemplify the potential of utilizing MALDI IMS for measuring not only quantitative drug distribution and target exposure but also drug metabolism and elimination in a single suite of experiments. SIGNIFICANCE STATEMENT: An integrated imaging approach utilizing matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) complemented with immunohistochemistry (IHC) and histology was used to address the question of target exposure at the cellular level. Localized quantification of the parent drug in the target organ and identification of potential metabolites in the context of tissue histology were also achieved in one experimental suite to support characterization of pharmacokinetic properties of the drug in the early discovery stage., (Copyright © 2024 by The American Society for Pharmacology and Experimental Therapeutics.)

Purpose: Trophoblast glycoprotein, the so-called 5T4, is an oncofetal antigen expressed in many different cancers. However, no 5T4-specific radioligand is employed in the clinic for non-invasive diagnosis. Thus, the aim of the current study was to develop a PET radiotracer for imaging 5T4 expression in preclinical and clinical stages., Methods: A VHH library was constructed by camel immunization. The specificity of the VHHs toward 5T4 antigen was screened through phage display biopanning and periplasmic extract enzyme-linked immunosorbent assay. 1,4,7-Triazacyclononane-1,4,7-triacetate acid (NOTA) derivative was conjugated to the selected VHH. After radiolabeling, microPET/CT and ex vivo biodistribution were conducted using BxPC-3 and MDA-MB-468 tumor-bearing mice. Cold VHH was co-injected with the tracer to challenge its binding in vivo. For the pilot clinical study, PET/CT images were acquired at 1 h after injection of tracer in patients with pathologically confirmed primary and metastatic tumors., Results: A library with a capacity of 1.2 × 10 12 colony-forming units was constructed after successful camel immunization. Nb1-40 with a median effect concentration of 0.43 nM was selected. After humanization, the resulting H006 maintained a high affinity towards 5T4. [ 68 Ga]Ga-NOTA-H006 with the molar activities of 6.48-54.2 GBq/µmol was prepared with high radiochemical purity (> 98%). Using [ 68 Ga]Ga-NOTA-H006, microPET/CT revealed a clear visualization of 5T4 expression in BxPC-3 tumor-bearing mice. Ex vivo biodistribution showed that the highest tumor-to-blood ratio (∼ 3-fold) and tumor-to-muscle ratio (∼ 5-fold) were achieved at 60 min post-injection. Co-injection of the cold H006 at a dose of 1.5 mg/kg significantly reduced the tumor uptake (p < 0.0001). In the pilot clinical study, [ 68 Ga]Ga-NOTA-H006 demonstrated its capacity to map 5T4-positive lesions in humans and yielded a mean effective dose of 3.4 × 10 - 2 mSv/MBq., Conclusions: [ 68 Ga]Ga-NOTA-H006, which can visualize 5T4 expression in vivo, has been successfully developed. This opens up opportunities for non-invasively studying 5T4 expression through nuclear medicine. Further clinical investigations are warranted to explore its clinical value in disease progression and companion diagnosis., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To compare the efficacy of traditional occlusal guides with computer-aided surgical simulation (CASS) guides in enhancing postoperative outcomes for patients with bimaxillary protrusion., Methods: This retrospective study evaluated 34 patients undergoing anterior maxillary and mandibular subapical osteotomy at the Plastic Surgery Hospital of the Chinese Academy of Medical Sciences. Fourteen patients were treated using traditional occlusal guides, whereas 20 patients were treated with CASS guides (median age 28.6 years, median follow-up 259 days). Pre and postoperative cephalometric indicators were measured using cephalometric software. Data analysis was conducted using SPSS 14.0, with significant differences determined at P < 0.05., Results: All 34 patients experienced primary healing without complications. Follow-up indicated significant improvements in key cephalometric measurements in the CASS group compared with the traditional group, including mandibular position (SNB angle, P < 0.001), jaw relationship (ANB angle, P < 0.001), facial angle (FH-NPo, P = 0.002), and condyle-to-sella distance (Co-S, P = 0.024). The CASS group also showed better aesthetic outcomes, with significant reductions in overjet (P = 0.012), overbite (P = 0.001), and improved alignment of upper and lower incisors (U1-L1 angle, P = 0.031)., Conclusion: CASS-guided surgery offers a superior alternative to traditional methods for treating bimaxillary protrusion, providing more precise and aesthetically pleasing results. This study highlights the significant advantages of using advanced digital simulation and 3-dimensional printing technologies in orthognathic surgery., Competing Interests: The authors report no conflicts of interest., (Copyright © 2024 by Mutaz B. Habal, MD.)

Background: Tumor-reactive T cells play a crucial role in anti-tumor responses, but T cells induced by DNA vaccination are time-consuming processes and exhibit limited anti-tumor efficacy. Therefore, we evaluated the anti-tumor effectiveness of reactive T cells elicited by electroporation (EP)-mediated DNA vaccine targeting epidermal growth factor receptor variant III (pEGFRvIII plasmid), in conjunction with adoptive cell therapy (ACT), involving the transfer of lymphocytes from a pEGFRvIII EP-vaccinated healthy donor., Methods: The validation of the established pEGFRvIII plasmid and EGFRvIII-positive cell model was confirmed through immunofluorescence and western blot analysis. Flow cytometry and cytotoxicity assays were performed to evaluate the functionality of antigen-specific reactive T cells induced by EP-mediated pEGFRvIII vaccines, ACT, or their combination. The anti-tumor effectiveness of EP-mediated pEGFRvIII vaccines alone or combined with ACT was evaluated in the B16F10-EGFRvIII tumor model., Results: EP-mediated pEGFRvIII vaccines elicited serum antibodies and a robust cellular immune response in both healthy and tumor-bearing mice. However, this response only marginally inhibited early-stage tumor growth in established tumor models. EP-mediated pEGFRvIII vaccination followed by adoptive transfer of lymphocytes from vaccinated healthy donors led to notable anti-tumor efficacy, attributed to the synergistic action of antigen-specific CD4 + Th1 cells supplemented by ACT and antigen-specific CD8 + T cells elicited by the EP-mediated DNA vaccination., Conclusions: Our preclinical studies results demonstrate an enhanced anti-tumor efficacy of EP-mediated DNA vaccination boosted with adoptively transferred, vaccinated healthy donor-derived allogeneic lymphocytes., (© 2024. The Author(s).)

Dementia has high incidence among the elderly, and Alzheimer's disease (AD) is the most common dementia. The procedure of AD diagnosis in clinics usually follows a standard routine consisting of different phases, from acquiring non-imaging tabular data in the screening phase to MR imaging and ultimately to PET imaging. Most of the existing AD diagnosis studies are dedicated to a specific phase using either single or multi-modal data. In this paper, we introduce a modality-flexible classification framework, which is applicable for different AD diagnosis phases following the clinical routine. Specifically, our framework consists of three branches corresponding to three diagnosis phases: 1) a tabular branch using only tabular data for screening phase, 2) an MRI branch using both MRI and tabular data for uncertain cases in screening phase, and 3) ultimately a PET branch for the challenging cases using all the modalities including PET, MRI, and tabular data. To achieve effective fusion of imaging and non-imaging modalities, we introduce an image-tabular transformer block to adaptively scale and shift the image and tabular features according to modality importance determined by the network. The proposed framework is extensively validated on four cohorts containing 6495 subjects. Experiments demonstrate that our framework achieves superior diagnostic performance than the other representative methods across various AD diagnosis tasks, and shows promising performance for all the diagnosis phases, which exhibits great potential for clinical application.

Reactive astrocytes play an important role in the development of Alzheimer's disease (AD). Here, we aimed to investigate the temporospatial relationships among monoamine oxidase-B, tau and amyloid-β (Aβ), translocator protein, and glucose metabolism by using multitracer imaging in AD transgenic mouse models. Positron emission tomography (PET) imaging with [ 18 F]SMBT-1 (monoamine oxidase-B), [ 18 F]florbetapir (Aβ), [ 18 F]PM-PBB3 (tau), [ 18 F]fluorodeoxyglucose (FDG), and [ 18 F]DPA-714 (translocator protein) was carried out in 5- and 10-month-old APP/PS1, 11-month-old 3×Tg mice, and aged-matched wild-type mice. The brain regional referenced standard uptake value (SUVR) was computed with the cerebellum as the reference region. Immunofluorescence staining was performed on mouse brain tissue slices. [ 18 F]SMBT-1 and [ 18 F]florbetapir SUVRs were greater in the cortex and hippocampus of 10-month-old APP/PS1 mice than in those of 5-month-old APP/PS1 mice and wild-type mice. No significant difference in the regional [ 18 F]FDG or [ 18 F]DPA-714 SUVRs was observed in the brains of 5- or 10-month-old APP/PS1 mice or wild-type mice. No significant difference in the SUVRs of any tracer was observed between 11-month-old 3×Tg mice and age-matched wild-type mice. A positive correlation between the SUVRs of [ 18 F]florbetapir and [ 18 F]DPA-714 in the cortex and hippocampus was observed among the transgenic mice. Immunostaining validated the distribution of MAO-B and limited Aβ and tau pathology in 11-month-old 3×Tg mice; and Aβ deposits in brain tissue from 10-month-old APP/PS1 mice. In summary, these findings provide in vivo evidence that an increase in astrocyte [ 18 F]SMBT-1 accompanies Aβ accumulation in APP/PS1 models of AD amyloidosis., (© 2024. The Author(s).)

Despite the potential of oral immunotherapy against food allergy, adverse reactions and loss of desensitization hinder its clinical uptake. Dysbiosis of the gut microbiota is implicated in the increasing prevalence of food allergy, which will need to be regulated to enable for an effective oral immunotherapy against food allergy. Here we report an inulin gel formulated with an allergen that normalizes the dysregulated ileal microbiota and metabolites in allergic mice, establishes allergen-specific oral tolerance and achieves robust oral immunotherapy efficacy with sustained unresponsiveness in food allergy models. These positive outcomes are associated with enhanced allergen uptake by antigen-sampling dendritic cells in the small intestine, suppressed pathogenic type 2 immune responses, increased interferon-γ + and interleukin-10 + regulatory T cell populations, and restored ileal abundances of Eggerthellaceae and Enterorhabdus in allergic mice. Overall, our findings underscore the therapeutic potential of the engineered allergen gel as a suitable microbiome-modulating platform for food allergy and other allergic diseases., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Lumbar disc herniation (LDH) is a prevalent condition in spinal surgery, and Traditional Chinese Medicine (TCM) acupuncture has gained clinical attention as a potential treatment for LDH in recent years., Objective: This study aimed to assess the therapeutic efficacy of acupuncture combined with acupoint massage in LDH patients., Methods: We enrolled a total of 135 LDH patients treated at our hospital from May 2021 to February 2023. Among them, 63 patients received acupuncture treatment (control group), while the remaining 72 received acupuncture combined with acupoint massage (observation group). We compared treatment efficacy and the time it took for lumbar stiffness, lower back and leg pain, bending and flexing difficulties, and other symptoms to disappear between the two groups. The Visual Analogue Scale (VAS) and Japanese Orthopedic Association Scoring System (JOA) were used to evaluate patients' pain levels and lumbar vertebral function before and after treatment. Additionally, we assessed patients using the Generic Quality of Life Inventory-74 (GQOL-74) and recorded their treatment satisfaction., Results: The observation group exhibited a slightly higher total effective rate compared to the control group, with a shorter time for the resolution of lumbar stiffness, lower back pain, leg pain, and other symptoms (P < .05). Furthermore, the observation group had lower VAS scores and higher JOA scores (P < .05). They also achieved higher GQOL-74 scores and reported greater treatment satisfaction (P < .05)., Conclusions: Acupuncture combined with acupoint massage effectively alleviated clinical symptoms and pain in LDH patients, demonstrating significant clinical utility.

Gene innovation plays an essential role in trait evolution. Rhizobial symbioses, the most important N 2 -fixing agent in agricultural systems that exists mainly in Leguminosae, is one of the most attractive evolution events. However, the gene innovations underlying Leguminosae root nodule symbiosis (RNS) remain largely unknown. Here, we investigated the gene gain event in Leguminosae RNS evolution through comprehensive phylogenomic analyses. We revealed that Leguminosae-gain genes were acquired by gene duplication and underwent a strong purifying selection. Kyoto Encyclopedia of Genes and Genomes analyses showed that the innovated genes were enriched in flavonoid biosynthesis pathways, particular downstream of chalcone synthase (CHS). Among them, Leguminosae-gain type Ⅱ chalcone isomerase (CHI) could be further divided into CHI1A and CHI1B clades, which resulted from the products of tandem duplication. Furthermore, the duplicated CHI genes exhibited exon-intron structural divergences evolved through exon/intron gain/loss and insertion/deletion. Knocking down CHI1B significantly reduced nodulation in Glycine max (soybean) and Medicago truncatula; whereas, knocking down its duplication gene CHI1A had no effect on nodulation. Therefore, Leguminosae-gain type Ⅱ CHI participated in RNS and the duplicated CHI1A and CHI1B genes exhibited RNS functional divergence. This study provides functional insights into Leguminosae-gain genetic innovation and sub-functionalization after gene duplication that contribute to the evolution and adaptation of RNS in Leguminosae., (© 2024 Institute of Botany, Chinese Academy of Sciences.)

Background: Root nodule symbiosis (RNS) is a fascinating evolutionary event. Given that limited genes conferring the evolution of RNS in Leguminosae have been functionally validated, the genetic basis of the evolution of RNS remains largely unknown. Identifying the genes involved in the evolution of RNS will help to reveal the mystery., Results: Here, we investigate the gene loss event during the evolution of RNS in Leguminosae through phylogenomic and synteny analyses in 48 species including 16 Leguminosae species. We reveal that loss of the Lateral suppressor gene, a member of the GRAS-domain protein family, is associated with the evolution of RNS in Leguminosae. Ectopic expression of the Lateral suppressor (Ls) gene from tomato and its homolog MONOCULM 1 (MOC1) and Os7 from rice in soybean and Medicago truncatula result in almost completely lost nodulation capability. Further investigation shows that Lateral suppressor protein, Ls, MOC1, and Os7 might function through an interaction with NODULATION SIGNALING PATHWAY 2 (NSP2) and CYCLOPS to repress the transcription of NODULE INCEPTION (NIN) to inhibit the nodulation in Leguminosae. Additionally, we find that the cathepsin H (CTSH), a conserved protein, could interact with Lateral suppressor protein, Ls, MOC1, and Os7 and affect the nodulation., Conclusions: This study sheds light on uncovering the genetic basis of the evolution of RNS in Leguminosae and suggests that gene loss plays an essential role., (© 2024. The Author(s).)

Most patients with metastatic prostate cancer eventually develop resistance to primary androgen deprivation therapy. To identify predictive biomarker for Abiraterone acetate/prednisone resistance, we screened alternative splice variants between responders and non-responders from the PROMOTE clinical study and pinned down the most significant variant, CENPK-delta8. Through preclinical patient-derived mouse xenograft (PDX) and 3D organoids obtained from responders and non-responders, as well as in vitro models, aberrant CENPK-delta8 expression was determined to link to drug resistance via enhanced migration and proliferation. The FLNA and FLOT1 were observed to specifically bind to CENK-delta8 rather than wild-type CENPK, underscoring the role of CENPK-delta8 in cytoskeleton organization and cell migration. Our study, leveraging data from the PROMOTE study, TCGA, and TCGA SpliceReq databases, highlights the important function of alternative splice variants in drug response and their potential to be prognostic biomarkers for improving individual therapeutic outcomes in precision medicine.

We aimed to investigate the effect of a polysaccharide from Tremella aurantialba on ulcerative colitis (UC), which targets ferroptosis in epithelial cells. TA 2-1 (127 kDa) was isolated from T. aurantialba and consisted of Man, Xyl, GlcA, Glc, Fuc and Rha with a molar ratio of 59.2: 23.2: 13.9: 1.6: 1.7: 0.4, exhibited a 1, 3-Man structure with branch chains of T-Xylp, 1,3-Xylp, 1,4-GlcAp, and T-Manp at its O-2 position. TA 2-1 (100 μg/mL) inhibited the cell viability of ferroptosis (19.8 %) in RLS3-induced Caco-2 cells and significantly ameliorated symptoms in the colons of mice with dextran sodium sulfate (DSS)-induced UC. TA 2-1 remarkably repaired the intestinal barrier by upregulating claudin-1 and zonula occludens-1 levels. Further analysis found TA 2-1 significantly suppressed lipid peroxidation by regulating ferroptosis-related proteins in UC mice, suggesting that its protective effects are partially mediated by inhibiting ferroptosis. Further analysis of the gut microbiota and fecal microbiota transplantation revealed TA 2-1 might relieve UC symptoms or inhibit ferroptosis by modulating the gut microbiota's composition or metabolites. Results suggest the protective effects of TA 2-1 on the intestinal barrier by inhibiting ferroptosis of epithelial cells, at least by regulating the gut microbiota, highlighting the potential of TA 2-1 in UC treatment., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

For background, Hirsutella sinensis , the only anamorphic fungus considered an effective substitute for Cordyceps sinensis , possesses immunoregulatory properties. However, the specific mechanism underlying the immunoregulatory function of Hirsutella sinensis remains unclear. The purpose is to investigate the therapeutic effects of Hirsutella sinensis alcohol extract (HSAE) on immune dysregulation and elucidate the underlying mechanisms involved. For methods, we established inflammatory and immunosuppression models in vitro and in vivo to evaluate the bidirectional immunoregulatory function of HSAE via qRT-PCR and immunoblotting. We also studied its potential mechanism via RNA sequencing and transcriptional analysis. We further established M1 and M2 cell models to explore the effect of HSAE on M1/M2 polarization using qRT-PCR, immunoblotting, and flow cytometry. For results, our data demonstrated enhanced proliferation, phagocytosis, and antipathogenic activities of macrophages. Treatment with HSAE led to increases in the proportions of CD3 + and CD4 + immune cells in cyclophosphamide-induced immunosuppressed mice. Additionally, HSAE reduced the lipopolysaccharide (LPS)-induced expression of Il1b , Il6 , Ifnb1 , and Cxcl10 by inhibiting the activation of the NF-κB and MAPK pathways in vitro and improved mouse survival by reducing the proportion of M1/M2 macrophages in septic mice. Finally, we found that HSAE inhibited M1 polarization by decreasing the expression of iNOS and CD86 and promoted M2 polarization by increasing the expression of ARG1 and CD206. For conclusions, our study provides evidence that HSAE has the potential to enhance immune responses and suppress excessive inflammation. These effects were realized by modulating macrophage polarization, providing novel insights into the fundamental mechanism underlying the bidirectional immunomodulatory effect of HSAE.

One of the most robust synthetic lethal interactions observed in multiple functional genomic screens has been dependency on PRMT5 in cancer cells with MTAP deletion. We report the discovery of the clinical stage MTA-cooperative PRMT5 inhibitor AMG 193, which preferentially binds PRMT5 in the presence of MTA and has potent biochemical and cellular activity in MTAP-deleted cells across multiple cancer lineages. In vitro, PRMT5 inhibition induces DNA damage, cell cycle arrest, and aberrant alternative mRNA splicing in MTAP-deleted cells. In human cell line and patient-derived xenograft models, AMG 193 induces robust antitumor activity and is well tolerated with no impact on normal hematopoietic cell lineages. AMG 193 synergizes with chemotherapies or the KRAS G12C inhibitor sotorasib in vitro, and combination treatment in vivo significantly inhibits tumor growth. AMG 193 is demonstrating promising clinical activity, including confirmed partial responses in patients with MTAP-deleted solid tumors from an ongoing phase 1/2 study.

To develop a promising selenium supplement that overcomes the instability and poor water dispersibility of selenium nanoparticles (SeNPs), we synthesized a series of amphiphilic octenyl succinic anhydride starch (OSAS) through esterification. As the degree of substitution (DS) increased, the particle size of OSAS micelles and the critical micelle concentration (CMC) decreased. FTIR and XRD analysis confirmed the successful introduction of octenyl succinic anhydride groups onto starch. Subsequently, OSAS micelles were used as carriers to synthesize SeNPs via in situ chemical reduction, forming SeNPs-loaded self-assembled starch nano-micelles (OSAS-SeNPs). The OSAS-SeNPs exhibited spherical dispersion in water with an average diameter of 116.1 ± 2.3 nm, contributed to enhanced hydrophobic interactions. TEM images showed a core-shell structure with SeNPs as the core and OSAS as the shell. FTIR results indicated hydrogen bonding interactions between OSAS and SeNPs. Due to the negatively charged OSAS shell and hydrogen bonding (OH⋯Se), OSAS-SeNPs remained non-aggregated for one month at room temperature, demonstrating remarkable stability. This study suggests that using OSAS can address the synthesis and stability issues of SeNPs, making it a potential selenium supplement candidate for further evaluation as an anticancer agent., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

AML is a malignant tumor derived from the hematopoietic system, which has a poor prognosis and its incidence is increasing recent years. LncRNAs bind to miRNAs as competitive endogenous RNAs to regulate the occurrence and progression of AML， with IL-6R playing a crucial role in hematological malignancies. However, the mechanism by which noncoding RNAs regulate IL6R expression in AML remains unclear. This study found that the AC010247.2/miR-125b-5p axis promotes AML progression by regulating IL-6R expression. Specifically, knocking down or inhibiting AC010247.2 and miR-125b-5p affected IL6R and its downstream genes. Mechanistically, AC010247.2 acts as a ceRNA for miR-125b-5p, influencing IL-6R expression. Additionally, AC010247.2's regulation of AML progression partially depends on miR-125b-5p. Notably, the AC010247.2/miR-125b-5p/IL6R axis serves as a better polygenic diagnostic marker for AML. Our study identifies a key ceRNA regulatory axis that modulates IL6R expression in AML, providing a reliable multigene diagnostic method and potential therapeutic target., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors. Published by Elsevier Ltd.)

The associations of synaptic loss with amyloid-β (Aβ) and tau pathology measured by positron emission tomography (PET) and plasma analysis in Alzheimer's disease (AD) patients are unknown. Seventy-five participants, including 26 AD patients, 19 mild cognitive impairment (MCI) patients, and 30 normal controls (NCs), underwent [ 18 F]SynVesT-1 PET/MR scans to assess synaptic density and [ 18 F]florbetapir and [ 18 F]MK6240 PET/CT scans to evaluate Aβ plaques and tau tangles. Among them, 19 AD patients, 12 MCI patients, and 29 NCs had plasma Aβ42/40 and p-tau181 levels measured by the Simoa platform. Twenty-three individuals, 6 AD patients, 4 MCI patients, and 13 NCs, underwent [ 18 F]SynVesT-1 PET/MRI and [ 18 F]MK6240 PET/CT scans during a one-year follow-up assessment. The associations of Aβ and tau pathology with cross-sectional and longitudinal synaptic loss were investigated using Pearson correlation analyses, generalized linear models and mediation analyses. AD patients exhibited lower synaptic density than NCs and MCI patients. In the whole cohort, global Aβ deposition was associated with synaptic loss in the medial (r = -0.431, p < 0.001) and lateral (r = -0.406, p < 0.001) temporal lobes. Synaptic density in almost all regions was related to the corresponding regional tau tangles independent of global Aβ deposition in the whole cohort and stratified groups. Synaptic density in the medial and lateral temporal lobes was correlated with plasma Aβ42/40 (r = 0.300, p = 0.020/r = 0.289, p = 0.025) and plasma p-tau 181 (r = -0.412, p = 0.001/r = -0.529, p < 0.001) levels in the whole cohort. Mediation analyses revealed that tau tangles mediated the relationship between Aβ plaques and synaptic density in the whole cohort. Baseline tau pathology was positively associated with longitudinal synaptic loss. This study suggested that tau burden is strongly linked to synaptic density independent of Aβ plaques, and also can predict longitudinal synaptic loss., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Symbiotic nodules comprise two classes, indeterminate and determinate, defined by the presence/absence of apical meristem and developmental zonation. Why meristem and zonation are absent from determinate nodules remains unclear. Here, we define cell types in developing soybean nodules, highlighting the undifferentiated infection zones and differentiated nitrogen-fixation zones. Auxin governs infection zone maintenance. GRETCHEN HAGEN 3 (GH3) enzymes deactivate auxin by conjugation and promote cell differentiation. gh3 mutants increased undifferentiated cells and enlarged infection zones. The central symbiosis-transcription factor NIN2a activates GH3.1 to reduce auxin levels and facilitates cell differentiation. High auxin promotes NIN2a protein accumulation and enhances signaling, further deactivating auxin and depleting infection zones. Our findings shed light on the NIN2a-GH3-auxin module that drives soybean nodule cell differentiation. This study challenges our understanding of determinate nodule development and proposes that the regulation of nodule zonation offers valuable insights into broader mechanisms of cell differentiation across plant species., Competing Interests: Declaration of interests Patents entitled “Soybean auxin conjugating enzyme GRETCHEN HAGEN 3 (GH3) gene family and their applications (202410456123.X)” have been applied for in China. X.C., T.T., Z.G., L.H., and J.C. are listed as inventors., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Recent advances in immunotherapy represent a breakthrough in solid tumor treatment but the existing data indicate that immunotherapy is not effective in improving the survival time of patients with glioblastoma. The tumor microenvironment (TME) exerts a series of inhibitory effects on immune effector cells, which limits the clinical application of immunotherapy. Growing evidence shows that phosphate and tension homology deleted on chromosome ten (PTEN) plays an essential role in TME immunosuppression of glioblastoma. Emerging evidence also indicates that targeting PTEN can improve the anti-tumor immunity in TME and enhance the immunotherapy effect, highlighting the potential of PTEN as a promising therapeutic target. This review summarizes the function and specific upstream and downstream targets of PTEN-associated immune cells in glioblastoma TME, providing potential drug targets and therapeutic options for glioblastoma., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Du, Zhang, Li, Li, Deng, Jia, Lei, Kan, Xie and Huang.)

Background: The nucleus basalis of Meynert (NBM) is known to play a crucial role in the development and pathogenesis of Alzheimer's Disease (AD), particularly the cholinergic system within the NBM. However, the relationship between synaptic loss in the NBM and the clinical profile of AD remains unclear., Methods: In our study, we included 44 Aβ-negative normal controls (CN) and 76 Aβ-positive participants with cognitive impairment (CI). All participants underwent structural and diffusion magnetic resonance imaging (MRI), as well as positron emission tomography (PET) imaging to measure synaptic vesicle glycoprotein 2 A (SV2A) levels (Trial registration: NCT05623124. Registered 21 November 2022). The SV2A standardized uptake value ratios (SUVR) distribution in the NBM of CN participants was used as the reference norm. We investigated the association between NBM synaptic density and clinical performance, traditional AD biomarkers, and white matter tracts that passed the NBM., Results: Participants with cognitive impairment (CI) who had NBM synaptic density below 1.5 standard deviations (SD) or 0.5 SD of the norm exhibited worse cognitive performance compared to cognitively normal (CN) individuals. Crucially, the extent of deviation in synaptic density from the norm was directly proportional to the severity of cognitive impairment and neurodegeneration biomarkers. Furthermore, among patients with cognitive impairment, synaptic loss in the NBM was associated with potential impairment in the density and organization of neurites within the white matter tracts connected to the NBM. Finally, neurite density index in the medial tracts may play a mediating role in the relationship between NBM synaptic density and MMSE scores., Conclusion: The extent that synaptic density in NBM deviated from the norm suggested the extent of worse cognitive performance and severe neurodegeneration. Furthermore, cognitive impairment associated with synaptic loss in the NBM may be mediated by its pathological impact on NBM white matter tracts., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

In recent years, shape memory polymers (SMPs) and self-healing polymers (SHPs) have been research hotspots in the field of smart polymers owing to their unique stimulus response mechanisms. Previous research on SHPs has primarily focused on contact repair. However, in instances where substantial cracks occur during practical use, autonomous closure becomes challenging, impeding effective repair. By integration of the shape memory effect (SME) with SHPs, physical wound closure can be achieved via the SME, facilitating subsequent chemical/physical repair processes and enhancing self-healing effectiveness. This article reviews key findings from previous research on shape memory-assisted self-healing (SMASH) materials and addresses the challenges and opportunities for future investigation.

Background: The physical function of elderly individuals reflects whether they have had a history of regular physical activity over the long term. Such indicators have been found to have a certain connection with cognitive function these years. However, there is limited research that associates it with mechanisms such as cerebral Aβ deposition. We aim to investigate this relationship and unveil the underlying mechanisms., Method: Physical function and cognition data of 4189 participants were obtained from the Chinese preclinical Alzheimer's disease study. Participants were divided into six groups according to disease severity. Among them, 1048 participants underwent the positron emission tomography-computed tomography (PET-CT) and plasma biomarker test. Grip strength and gait were combined into a score indicating physical function. Multiple linear regression models and logistic regression models were mainly used to conduct the analysis., Results: There was a significant positive correlation between physical function and cognitive function (R = 0.48, p < 0.001), independent of sex, age, apolipoprotein E-ε4 genotype, and disease stages (p < 0.001). Physical function was effective in distinguishing individuals with cognitive impairment from those without (AUC = 0.835). Physical function was negatively associated with brain Aβ deposition (p = 0.008) and brain Aβ had an intermediary effect (p < 0.01) on the association between physical function and cognition in women. This association was mainly evident in the lateral parietal, lateral temporal, posterior cingulate, frontal, occipital, and precuneus regions. Physical function was negatively associated with plasma neurofilament light-chain (Nfl) level (p < 0.001)., Conclusions: Physical function is strongly associated with cognitive function in the Chinese elderly, and brain Aβ deposition partly mediates the linkage in women. Plasma Nfl can be used as a potential target for exercise intervention in cognitive function. Improving physical function will contribute to the alleviation of cognition decline., (© 2024 The Author(s). CNS Neuroscience & Therapeutics published by John Wiley & Sons Ltd.)

Elevated homocysteine (Hcy) levels are detrimental to neuronal cells and contribute to cognitive dysfunction in rats. Mitochondria plays a crucial role in cellular energy metabolism. Interestingly, the damaging effects of Hcy in vivo and in vitro conditions exhibit distinct results. Herein, we aimed to investigate the effects of Hcy on mitochondrial function in primary neurons and PC12 cells and explore the underlying mechanisms involved. The metabolic intermediates of Hcy act as methyl donors and play important epigenetic regulatory roles. N6-methyldeoxyadenosine (6 mA) modification, which is enriched in mitochondrial DNA (mtDNA), can be mediated by methylase METTL4. Our study suggested that mitochondrial perturbation caused by Hcy in primary neurons and PC12 cells may be attributable to mtDNA 6 mA modification difference. Hcy could activate the expression of METTL4 within mitochondria to facilitate mtDNA 6 mA status, and repress mtDNA transcription, then result in mitochondrial dysfunction., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

As the cornerstone of tissue engineering and regeneration medicine research, developing a cost-effective and bionic extracellular matrix (ECM) that can precisely modulate cellular behavior and form functional tissue remains challenging. An artificial ECM combining polysaccharides and fibrillar proteins to mimic the structure and composition of natural ECM provides a promising solution for cardiac tissue regeneration. In this study, we developed a bionic hydrogel scaffold by combining a quaternized β-chitin derivative (QC) and fibrin-matrigel (FM) in different ratios to mimic a natural ECM. We evaluated the stiffness of those composite hydrogels with different mixing ratios and their effects on the growth of human umbilical vein endothelial cells (HUVECs). The optimal hydrogels, QCFM1 hydrogels were further applied to load HUVECs into nude mice for in vivo angiogenesis. Besides, we encapsulated human pluripotent stem cell-derived cardiomyocytes (hPSC-CMs) into QCFM hydrogels and employed 3D bioprinting to achieve batch fabrication of human-engineered heart tissue (hEHT). Finally, the myocardial structure and electrophysiological function of hEHT were evaluated by immunofluorescence and optical mapping. Designed artificial ECM has a tunable modulus (220-1380 Pa), which determines the different cellular behavior of HUVECs when encapsulated in these. QCFM1 composite hydrogels with optimal stiffness (800 Pa) and porous architecture were finally identified, which could adapt for in vitro cell spreading and in vivo angiogenesis of HUVECs. Moreover, QCFM1 hydrogels were applied in 3D bioprinting successfully to achieve batch fabrication of both ring-shaped and patch-shaped hEHT. These QCFM1 hydrogels-based hEHTs possess organized sarcomeres and advanced function characteristics comparable to reported hEHTs. The chitin-derived hydrogels are first used for cardiac tissue engineering and achieve the batch fabrication of functionalized artificial myocardium. Specifically, these novel QCFM1 hydrogels provided a reliable and economical choice serving as ideal ECM for application in tissue engineering and regeneration medicine., (© 2024 Wiley Periodicals LLC.)

Introduction: Linear-array endoscopic ultrasound (EUS) and narrow-band imaging (NBI) are both used to estimate the invasion depth of nonpedunculated rectal lesions (NPRLs). However, it is unclear which procedure is more accurate. This randomized controlled trial aimed to compare the diagnostic accuracy of linear EUS and NBI for estimating the invasion depth of NPRLs., Methods: This study is a single-center, randomized, tandem trial. Eligible patients with NPRLs were randomly assigned to A group (assessment with EUS followed by NBI) or B group (assessment with NBI followed by EUS). The invasion depth of each lesion was independently measured by each procedure and categorized as mucosal to slight submucosal (M-SM s , invasion depth <1,000 μm) or deep submucosal (SM d , invasion depth ≥1,000 μm) invasion, with postoperative pathology as the standard of measurement. The primary outcome was diagnostic accuracy, and secondary outcomes included sensitivity, specificity, and procedure time., Results: Eighty-six patients with NPRLs were enrolled, and 79 patients were finally analyzed, including 39 cases in the A group and 40 cases in the B group. Comparable diagnostic accuracies were observed between EUS and NBI (96.2% vs 93.7%, P = 0.625). EUS identified lesions with deep submucosal invasion with 81.8% sensitivity while that of NBI was 63.6% ( P = 0.500). The specificity of both EUS and NBI was 98.5%. The procedure time was also similar between EUS and NBI (5.90 ± 3.44 vs 6.4 ± 3.94 minutes, P = 0.450). Furthermore, the combined use of EUS and NBI did not improve diagnostic accuracy compared with EUS or NBI alone (94.9% vs 96.2% vs 93.7%, P = 0.333)., Discussion: Linear EUS and NBI measure the invasion depth of NPRLs with comparable accuracy. The combination of the 2 methods does not improve the diagnostic accuracy. Single NBI should be preferred, considering its simplicity and convenience in clinical practice., (Copyright © 2024 by The American College of Gastroenterology.)

This patient was an elderly patient with abdominal distension and shortness of breath. According to relevant examinations, his condition was initially considered to be related to cirrhosis, but pathological biopsy confirmed the diagnosis of noncirrhotic portal hypertension of unknown etiology. The portal vein pressure was significantly reduced after transjugular intrahepatic portosystemic shunt (TIPS). Nevertheless, the relief of the hydrothorax and ascites was not significant, and the numbness in both lower limbs gradually worsened. POEMS syndrome was ultimately diagnosed following a comprehensive examination. After two courses of bortezomib combined with dexamethasone, the patient died due to a systemic infection. The clinical symptoms of the patient were atypical, as was the presence of portal hypertension, which hindered the diagnosis of POEMS. Due to the patient's advanced age, the diagnosis was delayed, and the prognosis was poor. This case reminds clinicians that POEMS patients can also have portal hypertension as the main manifestation., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Xu, Jing, Zhu, Jiang, Fu, Xie, Li and Meng.)

The exchange of matter and energy between crust and mantle significantly influences the formation and development of oil, gas, and geothermal resources. Understanding how these exchanges impact these resources is crucial in geological science. In many oil-rich basins in China, significant accumulations of H 2 , CO 2 , geothermal energy, and other associated resources linked to deep mantle materials or geological processes have been discovered. Therefore, investigating the effects of crust-mantle material and energy exchanges on these resources is of utmost importance. This paper aims to systematically analyze the effects of mantle materials (e.g., H 2 , CO 2 , catalytic elements) and energy upwelling into basins. It synthesizes the impacts of various organic-inorganic interactions on hydrocarbon generation, evolution of organic source rocks, reservoir development, and the formation and accumulation of oil and gas. Finally, it proposes a mechanism detailing how interactions between mantle matter and energy influence specific resources. Simultaneously, this study employs numerical simulations to uncover the specific impact of magma intrusions on the geothermal field of surrounding rock formations. It demonstrates that magma chambers, continuously supplied with mantle energy, create regional thermal anomalies and facilitate the development of high-temperature geothermal resources. This underscores that mantle materials and energy not only significantly influence the generation of oil and gas but also govern the formation of geothermal resources and the evolution of thermal reservoirs. This research provides a theoretical foundation for understanding the subsequent formation of oil and gas resources under the influence of deep geological processes. Moreover, it furnishes a scientific basis for evaluating and exploring the symbiotic relationship between oil and gas resources and geothermal reservoirs., Competing Interests: The authors declare no competing financial interest., (© 2024 The Authors. Published by American Chemical Society.)

Background: Reactive astrocytes play an important role in the development of Alzheimer's disease and primary tauopathies. Here, we aimed to investigate the relationships between reactive astrocytes. Microgliosis and glucose metabolism with Tau and amyloid beta pathology by using multi-tracer imaging in widely used tauopathy and familial Alzheimer's disease mouse models., Results: Positron emission tomography imaging using [ 18 F]PM-PBB3 (tau), [ 18 F]florbetapir (amyloid-beta), [ 18 F]SMBT-1 (monoamine oxidase-B), [ 18 F]DPA-714 (translocator protein) and [ 18 F]fluorodeoxyglucose was carried out in 3- and 7-month-old rTg4510 tau mice, 5 × FAD familial Alzheimer's disease mice and wild-type mice. Immunofluorescence staining was performed to validate the pathological distribution in the mouse brain after in vivo imaging. We found increased regional levels of [ 18 F]PM-PBB3, [ 18 F]SMBT-1, and [ 18 F]DPA-714 and hypoglucose metabolism in the brains of 7-month-old rTg4510 mice compared to age-matched wild-type mice. Increased [ 18 F]SMBT-1 uptake was observed in the brains of 3, 7-month-old 5 × FAD mice, with elevated regional [ 18 F]florbetapir and [ 18 F]DPA-714 uptakes in the brains of 7-month-old 5 × FAD mice, compared to age-matched wild-type mice. Positive correlations were shown between [ 18 F]SMBT-1 and [ 18 F]PM-PBB3, [ 18 F]DPA-714 and [ 18 F]PM-PBB3 in rTg4510 mice, and between [ 18 F]florbetapir and [ 18 F]DPA-714 SUVRs in 5 × FAD mice., Conclusion: In summary, these findings provide in vivo evidence that reactive astrocytes, microglial activation, and cerebral hypoglucose metabolism are associated with tau and amyloid pathology development in animal models of tauopathy and familial Alzheimer's disease., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024. Published by Elsevier B.V.)

Purpose: Toludesvenlafaxine is a recently developed antidepressant that belongs to the triple reuptake inhibitor class. Despite the in vitro evidence that toludesvenlafaxine inhibits the reuptake of serotonin (5-HT), norepinephrine (NE) and dopamine (DA), there is no in vivo evidence that toludesvenlafaxine binds to DAT and increases DA level, a mechanism thought to contribute to its favorable clinical performance., Methods: Positron emission tomography/computed tomography (PET/CT) was used to examine the DAT binding capacity in healthy rats and human subjects and microdialysis was used to examine the striatal DA level in rats. [ 18 F]FECNT and [ 11 C]CFT were used as PET/CT radioactive tracer for rat and human studies, respectively., Results: In rats, 9 mg/kg of toludesvenlafaxine hydrochloride (i.v.) followed by an infusion of 3 mg/kg via minipump led to the binding rate to striatum DAT at 3.7 - 32.41% and to hypothalamus DAT at 5.91 - 17.52% during the 45 min scanning period. 32 mg/kg oral administration with toludesvenlafaxine hydrochloride significantly increased the striatal DA level with the AUC 0 - 180 min increased by 63.9%. In healthy volunteers, 160 mg daily toludesvenlafaxine hydrochloride sustained-release tablets for 4 days led to an average occupancy rates of DAT at 8.04% ± 7.75% and 8.09% ± 7.00%, respectively, in basal ganglion 6 h and 10 h postdose., Conclusion: These results represent the first to confirm the binding of toludesvenlafaxine to DAT in both rats and humans using PET/CT, and its elevation of brain DA level, which may help understand the unique pharmacological and functional effects of triple reuptake inhibitors such as toludesvenlafaxine., Gov Identifiers: NCT05905120. Registered 14 June 2023. (retrospectively registered)., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background & Aims: It has been revealed good nutritional status and no physical frailty, which are modifiable lifestyle factors, are linked to less cognitive decline and a lower risk of Alzheimer's disease (AD). We aimed to investigate the associations between nutritional status and physical frailty and plasma AD biomarkers, especially the Tau-associated biomarkers in older cognitively unimpaired (CU) adults with higher β-amyloid (Aβ) burden., Methods: The nutritional status and physical frailty were assessed via Mini-Nutritional Assessment Short-Form (MNA-SF) and Fried frailty index. The participants underwent the examination of plasma AD biomarkers and 18 F-florbetapir PET scan as well as 18 F-MK6240 PET in the validation cohort. Correlation and multiple linear regression analyses were used to investigate the associations between nutritional status and frailty and AD biomarkers., Results: Two cohorts were included in our study. A total of 129 participants with Aβ-PET positive were enrolled in the development cohort. Multiple linear regression analysis showed MNA-SF scores, normal nutritional status, Fried frailty index scores, frailty and some domains of frailty including weight loss, maximal grip strength and exhaustion were associated with plasma p-Tau-181. Furthermore, weight loss, Fried frailty index scores and frailty were associated with higher Aβ-PET standard uptake value ratio. We further performed subgroup analyses stratified by age, sex and apolipoprotein E ε4 genotype to investigate the beneficial characteristics of nutrition and frailty in the special subgroups. Validation cohort contained 38 Aβ-PET positive participants. MNA-SF scores, normal nutritional status, Fried frailty index scores and frailty were associated with Tau burden evaluated by 18 F-MK6240 PET Braak-like stages., Conclusions: Our data indicates that normal nutritional status and no physical frailty may be associated with expected trend of plasma AD biomarkers, especially less Tau pathology in older CU adults with Aβ deposition. Adjusting to these characteristics of nutrition and physical frailty may help reduce the risk of AD development., Competing Interests: Conflict of interest No potential conflicts of interests of all authors., (Copyright © 2024 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

A newly developed SV2A radiotracer, 18 F-SynVesT-1, was used in this study to investigate synaptic density and its association with Alzheimer's disease (AD) "A/T/N" biomarkers. The study included a cohort of 97 subjects, consisting of 64 patients with cognitive impairment (CI) and 33 individuals with normal cognition (CU). All subjects underwent 18 F-SynVesT-1 PET/MR and 18 F-florbetapir PET/CT scans. Additionally, a subgroup of individuals also underwent 18 F-MK-6240, 18 F-FDG PET/CT, plasma Aβ42/Aβ40 and p-tau181 tests. The differences in synaptic density between the groups and the correlations between synaptic density and AD "A/T/N" biomarkers were analyzed. The results showed that compared to the CU group, the CI with Aβ+ (CI+) group exhibited the most pronounced synapse loss in the hippocampus, with some loss also observed in the neocortex. Furthermore, synaptic density in the hippocampus and parahippocampal gyrus showed associations with AD biomarkers detected by both imaging and plasma tests in the CI group. The associations between synaptic density and FDG uptake and hippocampal volume were also observed in the CI+ group. In conclusion, the study demonstrated significant synaptic density loss, as measured by the promising tracer 18 F-SynVesT-1, and its close correlation with "A/T/N" biomarkers in patients with both Alzheimer's clinical syndrome and pathological changes., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Factors influencing recovery after decompression surgery for cauda equina syndrome (CES) are not completely identified. The authors aimed to investigate the most valuable predictors (MVPs) of poor postoperative recovery (PPR) in patients with CES and construct a nomogram for discerning those who will experience PPR., Methods: Three hundred fifty-six patients with CES secondary to lumbar degenerative diseases treated at Xijing Hospital were randomly divided into training ( N =238) and validation ( N =118) cohorts at a 2:1 ratio. Moreover, 92 patients from the 970 th Hospital composed the testing cohort. Least Absolute Shrinkage and Selection Operator regression (LASSO) was used for selecting MVPs. The nomogram was developed by integrating coefficients of MVPs in the logistic regression, and its discrimination, calibration, and clinical utility were validated in all three cohorts., Results: After 3 to 5 years of follow-up, the residual rates of bladder dysfunction, bowel dysfunction, sexual dysfunction, and saddle anesthesia were 41.9, 44.1, 63.7, and 29.0%, respectively. MVPs included stress urinary incontinence, overactive bladder, low stream, difficult defecation, fecal incontinence, and saddle anesthesia in order. The discriminatory ability of the nomogram was up to 0.896, 0.919, and 0.848 in the training, validation, and testing cohorts, respectively. Besides, the nomogram showed good calibration and clinical utility in all cohorts. Furthermore, the optimal cutoff value of the nomogram score for distinguishing those who will experience PPR was 148.02, above which postoperative outcomes tend to be poor., Conclusion: The first pretreatment nomogram for discerning CES patients who will experience PPR was developed and validated, which will aid clinicians in clinical decision-making., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Symbiotic nitrogen fixation is an energy-intensive process, to maintain the balance between growth and nitrogen fixation, high concentrations of nitrate inhibit root nodulation. However, the precise mechanism underlying the nitrate inhibition of nodulation in soybean remains elusive. In this study, CRISPR-Cas9-mediated knockout of GmNLP1 and GmNLP4 unveiled a notable nitrate-tolerant nodulation phenotype. GmNLP1b and GmNLP4a play a significant role in the nitrate-triggered inhibition of nodulation, as the expression of nitrate-responsive genes was largely suppressed in Gmnlp1b and Gmnlp4a mutants. Furthermore, we demonstrated that GmNLP1b and GmNLP4a can bind to the promoters of GmNIC1a and GmNIC1b and activate their expression. Manipulations targeting GmNIC1a and GmNIC1b through knockdown or overexpression strategies resulted in either increased or decreased nodule number in response to nitrate. Additionally, transgenic roots that constitutively express GmNIC1a or GmNIC1b rely on both NARK and hydroxyproline O-arabinosyltransferase RDN1 to prevent the inhibitory effects imposed by nitrate on nodulation. In conclusion, this study highlights the crucial role of the GmNLP1/4-GmNIC1a/b module in mediating high nitrate-induced inhibition of nodulation., (© 2024 Society for Experimental Biology and John Wiley & Sons Ltd.)

Purpose: The cluster of differentiation (CD70) is a potential biomarker of clear cell renal cell carcinoma (ccRCC). This study aims to develop CD70-targeted immuno-positron emission tomography/computed tomography (immunoPET/CT) imaging tracers and explore the diagnostic value in preclinical studies and the potential value in detecting metastases in ccRCC patients., Methods: Four novel CD70-specific single-domain antibodies (sdAbs) were produced and labelled with 18 F by the aluminium fluoride restrained complexing agent (AlF-RESCA) method to develop radiotracers. The visualisation properties of the tracers were evaluated in a subcutaneous ccRCC patient-derived xenograft (PDX) model. In a registered prospective clinical trial (NCT06148220), six patients with pathologically confirmed RCC were included and underwent immunoPET/CT examination exploiting one of the developed tracers (i.e., [ 18 F]RCCB6)., Results: We engineered four sdAbs (His-tagged RCCB3 and RCCB6, His-tag-free RB3 and RB6) specifically targeting recombinant human CD70 without cross-reactivity to murine CD70. ImmunoPET/CT imaging with [ 18 F]RCCB3 and [ 18 F]RCCB6 demonstrated a high tumour-to-background ratio in a subcutaneous ccRCC PDX model, with the latter showing better diagnostic potential supported by higher tumour uptake and lower bone accumulation. In comparison, [ 18 F]RB6, developed by sequence optimisation, has significantly lower kidney accumulation than that of [ 18 F]RCCB6. In a pilot translational study, [ 18 F]RCCB6 immunoPET/CT displayed ccRCC metastases in multiple patients and demonstrated improved imaging contrast and diagnostic value than 18 F-FDG PET/CT in a patient with ccRCC., Conclusion: The work successfully developed a series of CD70-targeted immunoPET/CT imaging tracers. Of them, [ 18 F]RCCB6 clearly and specifically identified inoculated ccRCCs in preclinical studies. Clinical translation of [ 18 F]RCCB6 suggests potential for identifying recurrence and/or metastasis in ccRCC patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Here we disclose a CuB-catalyzed reaction between aurone-derived α,β-unsaturated imines and styrenes to produce 2-substituted benzofuran derivatives bearing both the γ-boryl functionality and α,β-unsymmetric stereogenic centers. The reaction represents the first transition-metal-catalyzed unsymmetric 1,4-Michael additions of azadienes, which would enrich the arsenal of CuB catalysis in organic synthesis. In addition, the synthetically versatile boron-alkylated products can be elaborated by chemical transformations to useful optically active benzofuran heterocycles.

Background: Anti-PD-1 therapy and chemotherapy is a recommended first-line treatment for recurrent or metastatic nasopharyngeal carcinoma, but the role of PD-1 blockade remains unknown in patients with locoregionally advanced nasopharyngeal carcinoma. We assessed the addition of sintilimab, a PD-1 inhibitor, to standard chemoradiotherapy in this patient population., Methods: This multicentre, open-label, parallel-group, randomised, controlled, phase 3 trial was conducted at nine hospitals in China. Adults aged 18-65 years with newly diagnosed high-risk non-metastatic stage III-IVa locoregionally advanced nasopharyngeal carcinoma (excluding T3-4N0 and T3N1) were eligible. Patients were randomly assigned (1:1) using blocks of four to receive gemcitabine and cisplatin induction chemotherapy followed by concurrent cisplatin radiotherapy (standard therapy group) or standard therapy with 200 mg sintilimab intravenously once every 3 weeks for 12 cycles (comprising three induction, three concurrent, and six adjuvant cycles to radiotherapy; sintilimab group). The primary endpoint was event-free survival from randomisation to disease recurrence (locoregional or distant) or death from any cause in the intention-to-treat population. Secondary endpoints included adverse events. This trial is registered with ClinicalTrials.gov (NCT03700476) and is now completed; follow-up is ongoing., Findings: Between Dec 21, 2018, and March 31, 2020, 425 patients were enrolled and randomly assigned to the sintilimab (n=210) or standard therapy groups (n=215). At median follow-up of 41·9 months (IQR 38·0-44·8; 389 alive at primary data cutoff [Feb 28, 2023] and 366 [94%] had at least 36 months of follow-up), event-free survival was higher in the sintilimab group compared with the standard therapy group (36-month rates 86% [95% CI 81-90] vs 76% [70-81]; stratified hazard ratio 0·59 [0·38-0·92]; p=0·019). Grade 3-4 adverse events occurred in 155 (74%) in the sintilimab group versus 140 (65%) in the standard therapy group, with the most common being stomatitis (68 [33%] vs 64 [30%]), leukopenia (54 [26%] vs 48 [22%]), and neutropenia (50 [24%] vs 46 [21%]). Two (1%) patients died in the sintilimab group (both considered to be immune-related) and one (<1%) in the standard therapy group. Grade 3-4 immune-related adverse events occurred in 20 (10%) patients in the sintilimab group., Interpretation: Addition of sintilimab to chemoradiotherapy improved event-free survival, albeit with higher but manageable adverse events. Longer follow-up is necessary to determine whether this regimen can be considered as the standard of care for patients with high-risk locoregionally advanced nasopharyngeal carcinoma., Funding: National Natural Science Foundation of China, Key-Area Research and Development Program of Guangdong Province, Natural Science Foundation of Guangdong Province, Overseas Expertise Introduction Project for Discipline Innovation, Guangzhou Municipal Health Commission, and Cancer Innovative Research Program of Sun Yat-sen University Cancer Center., Translation: For the Chinese translation of the abstract see Supplementary Materials section., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Flat electronic bands are expected to show proportionally enhanced electron correlations, which may generate a plethora of novel quantum phases and unusual low-energy excitations. They are increasingly being pursued in d-electron-based systems with crystalline lattices that feature destructive electronic interference, where they are often topological. Such flat bands, though, are generically located far away from the Fermi energy, which limits their capacity to partake in the low-energy physics. Here we show that electron correlations produce emergent flat bands that are pinned to the Fermi energy. We demonstrate this effect within a Hubbard model, in the regime described by Wannier orbitals where an effective Kondo description arises through orbital-selective Mott correlations. Moreover, the correlation effect cooperates with symmetry constraints to produce a topological Kondo semimetal. Our results motivate a novel design principle for Weyl Kondo semimetals in a new setting, viz. d-electron-based materials on suitable crystal lattices, and uncover interconnections among seemingly disparate systems that may inspire fresh understandings and realizations of correlated topological effects in quantum materials and beyond., (© 2024. The Author(s).)

Assessing programmed death ligand-1 (PD-L1) expression in non-small cell lung cancer (NSCLC), particularly in metastatic cases, remains challenging. In this study, surface plasmon resonance (SPR) analysis and [ 68 Ga]Ga-DOTA-WL12 micro-PET/CT imaging are performed. [ 68 Ga]Ga-DOTA-WL12 PET/CT and [ 18 F]FDG PET/CT are performed on a cohort of 20 patients with NSCLC. Semi-quantitative assessments include SUVmax, metabolic tumor volume (MTV), total lesion glycolysis (TLG), and target-to-background ratio (TBR). DOTA-WL12 exhibits robust PD-L1 binding with a KD value of 0.2 nM. Subsequent human studies reveal significant correlations between PD-L1 expression and the [ 68 Ga]Ga-DOTA-WL12 SUVmax in primary and metastatic lesions, surpassing the [ 18 F]FDG results (r = 0.8889, p <0.0001 vs r = 0.0469, p = 0.8127). Notably, [ 68 Ga]Ga-DOTA-WL12 imaging discerned SUVmax and TBR differences between PD-L1 TPS ≤1% and PD-L1 TPS > 1% groups (p all <0.001). In an NSCLC patient with brain metastases, [ 68 Ga]Ga-DOTA-WL12 shows a SUVmean of 0.04 in the brain background, with TBR values of 17 and 23, underscoring its potential for detecting brain metastases. The study provides initial evidence for the clinical utility of [ 68 Ga]Ga-DOTA-WL12 PET/CT for lesion detection, immunotherapy selection, and therapeutic efficacy evaluation in PD-L1-expressing NSCLC, demonstrating its potential as a valuable tool in NSCLC research and management., (© 2024 Wiley‐VCH GmbH.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. We previously reported comparable 3-year regional relapse-free survival (RRFS) using elective upper-neck irradiation (UNI) in N0-1 nasopharyngeal carcinoma (NPC) compared with standard whole-neck irradiation (WNI). Here, we present the prespecified 5-year overall survival (OS), RRFS, late toxicity, and additional analyses. In this randomized trial, patients received UNI (n = 224) or WNI (n = 222) for an uninvolved neck. After a median follow-up of 74 months, the UNI and WNI groups had similar 5-year OS (95.9% v 93.1%, hazard ratio [HR], 0.63 [95% CI, 0.30 to 1.35]; P = .24) and RRFS (95.0% v 94.9%, HR, 0.96 [95% CI, 0.43 to 2.13]; P = .91) rates. The 5-year disease-free survivors in the UNI group had a lower frequency of hypothyroidism (34% v 48%; P = .004), neck tissue damage (29% v 46%; P < .001), dysphagia (14% v 27%; P = .002), and lower-neck common carotid artery stenosis (15% v 26%; P = .043). The UNI group had higher postradiotherapy circulating lymphocyte counts than the WNI group (median: 400 cells/μL v 335 cells/μL, P = .007). In conclusion, these updated data confirmed that UNI of the uninvolved neck is a standard of care in N0-1 NPC, providing outstanding efficacy and reduced long-term toxicity, and might retain more immune function.

Neuroinflammation plays an important role in Alzheimer's disease and primary tauopathies. The aim of the current study was to map [ 18 F]GSK1482160 for imaging of purinergic P2X7R in Alzheimer's disease and primary tauopathy mouse models. Small animal PET was performed using [ 18 F]GSK1482160 in widely used mouse models of Alzheimer's disease (APP/PS1, 5×FAD, and 3×Tg), 4-repeat tauopathy (rTg4510) mice, and age-matched wild-type mice. Increased uptake of [ 18 F]GSK1482160 was observed in the brains of 7-month-old rTg4510 mice compared to wild-type mice and compared to 3-month-old rTg4510 mice. A positive correlation between hippocampal tau [ 18 F]APN-1607 and [ 18 F]GSK1482160 uptake was found in rTg4510 mice. No significant differences in the uptake of [ 18 F]GSK1482160 was observed for APP/PS1 mice, 5×FAD mice, or 3×Tg mice. Immunofluorescence staining further indicated the distribution of P2X7Rs in the brains of 7-month-old rTg4510 mice with accumulation of tau inclusion. These findings provide in vivo imaging evidence for an increased level of P2X7R in the brains of tauopathy mice.

The stimulator of interferon genes (STING), an integral adaptor protein in the DNA-sensing pathway, plays a pivotal role in the innate immune response against infections. Additionally, it presents a valuable therapeutic target for infectious diseases and cancer. We observed that fangchinoline (Fan), a bis-benzylisoquinoline alkaloid (BBA), effectively impedes the replication of vesicular stomatitis virus (VSV), encephalomyocarditis virus (EMCV), influenza A virus (H1N1), and herpes simplex virus-1 (HSV-1) in vitro . Fan treatment significantly reduced the viral load, attenuated tissue inflammation, and improved survival in a viral sepsis mouse model. Mechanistically, Fan activates the antiviral response in a STING-dependent manner, leading to increased expression of interferon (IFN) and interferon-stimulated genes (ISGs) for potent antiviral effects in vivo and in vitro. Notably, Fan interacts with STING, preventing its degradation and thereby extending the activation of IFN-based antiviral responses. Collectively, our findings highlight the potential of Fan, which elicits antiviral immunity by suppressing STING degradation, as a promising candidate for antiviral therapy., Competing Interests: The authors declare that there are no conflicts of interest., (© 2024 Published by Elsevier B.V. on behalf of Xi’an Jiaotong University.)

Nitric oxide (NO) donating drugs such as organic nitrates have been used to treat cardiovascular diseases for more than a century. These donors primarily produce NO systemically. It is however sometimes desirable to control the amount, location, and time of NO delivery. We present the design of a novel pH-sensitive NO release system that is achieved by the synthesis of dipeptide diphenylalanine (FF) and graphene oxide (GO) co-assembled hybrid nanosheets (termed as FF@GO) through weak molecular interactions. These hybrid nanosheets were characterised by using X-ray diffraction, Raman spectroscopy, Fourier transform infrared spectroscopy, zeta potential measurements, X-ray photoelectron spectroscopy, scanning and transmission electron microscopies. The weak molecular interactions, which include electrostatic, hydrogen bonding and π-π stacking, are pH sensitive due to the presence of carboxylic acid and amine functionalities on GO and the dipeptide building blocks. Herein, we demonstrate that this formulation can be loaded with NO gas with the dipeptide acting as an arresting agent to inhibit NO burst release at neutral pH; however, at acidic pH it is capable of releasing NO at the rate of up to 0.6 μM per minute, comparable to the amount of NO produced by healthy endothelium. In conclusion, the innovative conjugation of dipeptide with graphene can store and release NO gas under physiologically relevant concentrations in a pH-responsive manner. pH responsive NO-releasing organic-inorganic nanohybrids may prove useful for the treatment of cardiovascular diseases and other pathologies., Competing Interests: Declaration of competing interest Authors declare no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: The objectives were to assess (i) the quality of theory implementation, (ii) the application of behavior change techniques, and (iii) the effectiveness of theory-based interventions in promoting physical activity in pregnant women and improving maternal and neonatal outcomes., Methods: A systematic search was conducted across 8 databases (Cumulative Index to Nursing and Allied Health Literature, the Cochrane Library, EMBASE, MEDLINE, APA PsycINFO, PubMed, SPORTDiscus, and Web of Science) to identify randomized controlled trials published from database inception to 8 July 2023. The Cochrane risk-of-bias 2.0 tool was used to evaluate the quality of the included studies. The theory coding scheme was used to measure the quality of theory implementation, and behavior change techniques were coded according to behavior change taxonomy (version 1). The meta-analysis was performed using RevMan 5.3. The Grading of Recommendations, Assessment, Development, and Evaluation Approach was used to assess the certainty of evidence., Results: Eleven studies met the study criteria. Nine studies were based on one theory, while two studies were based on a combination of two theories. The quality of theory implementation was generally moderate. A total of 24 unique behavior change techniques were extracted. The most commonly used types of behavior change techniques were 'instruction on how to perform the behavior' (n = 9), 'goal setting' (behavior) (n = 8), 'action planning' (n = 7), and 'information about health consequences' (n = 7). Theory-based interventions significantly improved moderate-to-vigorous physical activity (standardized mean difference (SMD) = 0.17, 95 % confidence interval (CI) [0.04, 0.30], P = 0.01; moderate certainty of evidence), reduced the average gestational weight gain per week (mean difference (MD) = -0.06, 95 % CI [-0.11, -0.01], P = 0.02; moderate certainty of evidence), and decreased the incidence of gestational diabetes mellitus (risk ratio (RR) = 0.64, 95 % CI [0.46, 0.89], P = 0.008; high certainty of evidence). However, the effects of theory-based interventions on total physical activity, total gestational weight gain and the incidence of gestational hypertension and preterm delivery were unclear (P > 0.05)., Conclusions: (i) Most of the studies exhibited a moderate level of theory implementation quality. (ii) The use of theories varies, but common behavior change techniques were found across studies. (iii) Theory-based interventions can improve physical activity and maternal and neonatal outcomes and appear to be safe. Appropriate health behavior theories and behavior change techniques should be fully utilized in future interventions., Registration: PROSPERO: CRD42023440886., Tweetable Abstract: Theory-based interventions can improve physical activity and maternal and neonatal outcomes and appear to be safe. Appropriate health behavior theories and behavior change techniques should be fully utilized in the development of future interventions., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Introduction: Metabotropic glutamate receptor 5 (mGluR5) is involved in regulating integrative brain function and synaptic transmission. Aberrant mGluR5 signaling and relevant synaptic failure play a key role in the pathophysiological mechanism of Alzheimer's disease (AD)., Methods: Ten cognitively impaired (CI) individuals and 10 healthy controls (HCs) underwent [ 18 F]SynVesT-1 and [ 18 F]PSS232 positron emission tomography (PET)/magnetic resonance to assess synaptic density and mGluR5 availability. The associations between mGluR5 availability and synaptic density were examined. A mediation analysis was performed to investigate the possible mediating effects of mGluR5 availability and synaptic loss on the relationship between amyloid deposition and cognition., Results: CI patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and cognition., Conclusions: Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD and are closely linked., Highlights: Cognitively impaired patients exhibited lower mGluR5 availability and synaptic density in the medial temporal lobe than HCs. Reductions in mGluR5 availability and synaptic density exhibit similar spatial patterns in AD. Regional synaptic density was closely associated with regional mGluR5 availability. mGluR5 availability and synaptic loss partially mediated the relationship between amyloid deposition and global cognition. With further research, modulating mGluR5 availability might be a potential therapeutic strategy for improving synaptic function in AD., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Introduction: We investigated the association between white matter hyperintensities (WMH) and regional cortical thickness, amyloid and tau deposition, and synaptic density in the WMH-connected cortex using multimodal images., Methods: We included 107 participants (59 with Alzheimer's disease [AD]; 27 with mild cognitive impairment; 21 cognitively normal controls) with amyloid beta (Aβ) positivity on amyloid positron emission tomography (PET). The cortex connected to WMH was identified using probabilistic tractography., Results: We found that WMH connected to the cortex with more severe regional degeneration as measured by cortical thickness, Aβ and tau deposition, and synaptic vesicle glycoprotein 2 A (SV2A) density using 18 F-SynVesT-1 PET. In addition, higher ratios of Aβ in the deep WMH-connected versus WMH-unconnected cortex were significantly related to lower cognitive scores. Last, the cortical thickness of WMH-connected cortex reduced more than WMH-unconnected cortex over 12 months., Discussion: Our results suggest that WMH may be associated with AD-intrinsic processes of degeneration, in addition to vascular mechanisms., Highlights: We studied white matter hyperintensities (WMHs) and WMH-connected cortical changes. WMHs are associated with more severe regional cortical degeneration. Findings suggest WMHs may be associated with Alzheimer's disease-intrinsic processes of degeneration., (© 2024 The Authors. Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

The gene-encoding carboxylesterase ( TM1022 ) from the hyperthermophilic bacterium Thermotoga maritima ( T. maritima ) was cloned and expressed in Escherichia coli Top10 and BL21 (DE3). Recombinant TM1022 showed the best activity at pH 8.0 and 85 °C and retained 57% activity after 8 h cultivation at 90 °C. TM1022 exhibited good stability at pH 6.0-9.0, maintaining 53% activity after incubation at pH 10.0 and 37 °C for 6 h. The esterase TM1022 exhibited the optimum thermo-alkali stability and k cat / K m (598.57 ± 19.97 s -1 mM -1 ) for p N-C4. TM1022 hydrolyzed poly(ethylene terephthalate) (PET) degradation intermediates, such as bis(2-hydroxyethyl) terephthalate (BHET) and mono(2-hydroxyethyl) terephthalate (MHET). The K m , k cat , and k cat / K m values for BHET were 0.82 ± 0.01 mM, 2.20 ± 0.02 s -1 , and 2.67 ± 0.02 mM -1 s -1 , respectively; those for MHET were 2.43 ± 0.07 mM, 0.04 ± 0.001 s -1 , and 0.02 ± 0.001 mM -1 s -1 , respectively. When purified TM1022 was added to the cutinase BhrPETase, hydrolysis of PET from drinking water bottle tops produced pure terephthalic acids (TPA) with 166% higher yield than those obtained after 72 h of incubation with BhrPETase alone as control. The above findings demonstrate that the esterase TM1022 from T. maritima has substantial potential for depolymerizing PET into monomers for reuse.

Flax powdery mildew (PM), caused by Oidium lini , is a globally distributed fungal disease of flax, and seriously impairs its yield and quality. To data, only three resistance genes and a few putative quantitative trait loci (QTL) have been reported for flax PM resistance. To dissect the resistance mechanism against PM and identify resistant genetic regions, based on four years of phenotypic datasets (2017, 2019 to 2021), a genome-wide association study (GWAS) was performed on 200 flax core accessions using 674,074 SNPs and 7 models. A total of 434 unique quantitative trait nucleotides (QTNs) associated with 331 QTL were detected. Sixty-four loci shared in at least two datasets were found to be significant in haplotype analyses, and 20 of these sites were shared by multiple models. Simultaneously, a large-effect locus ( qDI 11.2 ) was detected repeatedly, which was present in the mapping study of flax pasmo resistance loci. Oil flax had more QTL with positive-effect or favorable alleles (PQTL) and showed higher PM resistance than fiber flax, indicating that effects of these QTL were mainly additive. Furthermore, an excellent resistant variety C120 was identified and can be used to promote planting. Based on 331 QTLs identified through GWAS and the statistical model GBLUP, a genomic selection (GS) model related to flax PM resistance was constructed, and the prediction accuracy rate was 0.96. Our results provide valuable insights into the genetic basis of resistance and contribute to the advancement of breeding programs., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Zhu, Li, Guo, Li, Xue, Jiang, Yan, Xie, Ning and Xie.)