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Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world. Triticum timopheevii (2n = 4x = 28) is an allotetraploid wheat wild relative species containing the At and G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly of T. timopheevii accession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb and included the mitochondrial and plastid genome sequences. Genome annotation predicted 166,325 gene models including 70,365 genes with high confidence. DNA methylation analysis showed that the G genome had on average more methylated bases than the At genome. In summary, the T. timopheevii genome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.

Objective To explore the clinical characteristics of acute attacks of bronchial asthma （BA） in children in Kashgar region， and analyze the impact of 25-hydroxyvitamin D3 （25（OH）D3） levels on disease severity. Methods Children with acute BA attacks， aged 6-14 years， admitted to a certain thirdtier A-level Hospital of Kashgar were enrolled and divided into different groups according to disease severity （mild， moderate and severe） and 25（OH）D3 levels （normal， insufficiency and deficiency）. Clinical characteristics were compared among different groups. The correlation between 25（OH）D3 levels and disease severity was analyzed. Results A total of 112 children were enrolled， with a male-to-female ratio of 2.61∶1， with a median age of 9.0 （7.0-11.0） years old. The highest incidence was found in spring （42.9%）. The positive rate of allergens is 74.1%（83/112）， with inhaled allergens as the main type （89.1%）， and the tree combination had the highest positive rate （47.0%）.Based on disease severity， 36 cases were assigned into the mild group， 51 cases in the moderate group， and 25 cases in the severe group. As the disease severity was aggravated， the forced vital capacity （FVC）， forced expiratory volume at 1 second （FEV1）， and the ratio of FEV1 to FVC（FEV1/FVC） were gradually decreased （all P <0.001）. The eosinophil （EOS） count in the severe group was higher than that in the mild group （P < 0.05）. According to 25（OH）D3levels， 28 cases had normal 25（OH）D3 levels， 21 cases with insufficient 25（OH）D3 levels， and 35 cases with 25（OH）D3 deficiency. The FVC， FEV1， FEV1/FVC， and peak expiratory flow （PEF） in the 25（OH）D3 deficiency group were significantly lower than those in the insufficient and normal 25（OH）D3 groups （all P < 0.05）. The disease severity significantly differed among three groups （H = 9.538， P = 0.008）. Serum 25 （OH） D3 levels were negatively correlated with the severity of BA attacks （τ = -0.304， P =0.002）. Conclusions Spring is the peak season of acute attacks of BA in school-age children from Kashgar. Inhaled allergens are mainly composed of tree combination. As the severity of this condition deteriorates， lung function of the affected children are gradually declined. Serum 25 （OH） D3 levels are associated with lung function and the severity of acute attacks in children with BA.

The subspecies Abrus pulchellus subsp. mollis exhibits pharmacological properties akin to the traditional Chinese medicinal plant Abri Herba (A. pulchellus subsp. cantoniensis (Hance) Verdc.). In this report, we unveil the plastid genome of A. pulchellus subsp. mollis. The genome spans 156,322 base pairs (bp), comprising a large single-copy (LSC) region of 86,633 bp, a small single-copy (SSC) region of 18,219 bp, and two distinct inverted repeat regions (IRs) of 25,735 bp each. Annotation process cataloged a total of 111 genes within this genome, including 77 protein-coding genes, 30 transfer RNA (tRNA) genes, and four ribosomal RNA (rRNA) genes. The overall guanine-cytosine (GC) content of the plastome is 35.5%. Phylogenetic analysis utilizing maximum-likelihood (ML) based on 16 complete plastid genomes reveals a close clustering of three Abrus taxa, namely A. pulchellus subsp. mollis, A. pulchellus subsp. cantoniensis, and A. precatorius. Notably, A. pulchellus subsp. cantoniensis clusters with A. precatorius as a sister group, distinct from A. pulchellus subsp. mollis. These findings highlight significant differences between the plastid genomes of the two subspecies, laying the foundation for future research on the identification of medicinal herbs and germplasm resources related to these subspecies.

"Objective To explore the correlation between triglyceride glucose (TyG) index and arteriosclerosis in natural population, and whether TyG index could be used as a predictor of poor prognosis of cardio-cerebrovascular diseases. Methods A cross-sectional study was conducted on 4 355 adults recruited from the natural population in the community of Gaoyou City, Jiangsu Province from 2009 to 2010. According to the TyG index quartiles, they were divided into Q1 group (TyG≤8.19,n=1 100), Q2 group (8.19＜TyG≤8.55,n=1 080), Q3 group (8.55＜TyG≤8.99,n=1 103), Q4 group (TyG＞8.99,n=1 072). Taking brachial-ankle pulse wave conduction velocity (baPWV) as the observation index of arteriosclerosis, the correlation between TyG index and baPWV was analyzed by univariate and multivariate linear regression. A restricted cubic spline function diagram with multivariate correction was performed to explore whether there was a nonlinear correlation between TyG index and baPWV. Results After adjusting for confounding factors, compared with Q1 group, the regression coefficient and its 95%CI of TyG index affecting baPWV among Q2, Q3 and Q4 groups were 0.11 (-0.07-0.29), 0.41 (0.23-0.59) and 0.97 (0.78-1.16), respectively (trend testP＜0.01). Restricted cubic spline analysis showed a linear positive correlation between TyG index and baPWV. The mediator effect analysis also showed that TyG index partially mediated the impact on baPWV through inflammation. Conclusion TyG index is linearly and positively correlated with atherosclerosis."

Abstract Background Microbial infection and colonization are frequently associated with disease progression and poor clinical outcomes in bronchiectasis. Identification of pathogen spectrum is crucial for precision treatment at exacerbation of bronchiectasis. Methods We conducted a prospective cohort study in patients with bronchiectasis exacerbation onset and stable state. Bronchoalveolar lavage fluid (BALF) was collected for conventional microbiological tests (CMTs) and metagenomic Next-Generation Sequencing (mNGS). Bronchiectasis patients were monitored for documenting the time to the next exacerbation during longitudinal follow-up. Results We recruited 168 eligible participants in the exacerbation cohorts, and 38 bronchiectasis patients at stable state at longitudinal follow-up. 141 bronchiectasis patients at exacerbation onset had definite or probable pathogens via combining CMTs with mNGS reports. We identified that Pseudomonas aeruginosa, non-tuberculous mycobacteria, Haemophilus influenzae, Nocardia spp, and Staphylococcus aureus were the top 5 pathogens with a higher detection rate in our cohorts via combination of CMTs and mNGS analysis. We also observed strong correlations of Pseudomonas aeruginosa, Haemophilus influenzae, non-tuberculous mycobacteria with disease severity, including the disease duration, Bronchiectasis Severity Index, and lung function. Moreover, the adjusted pathogenic index of potential pathogenic microorganism negatively correlated (r = -0.7280, p

Dendritic cells (DCs) are the most potent professional antigen-presenting cells (APCs), which play a pivotal role in inducing either inflammatory or tolerogenic response based on their subtypes and environmental signals. DCs are critical for initiation and progression of multiple sclerosis (MS). Induction of tolerogenic DCs (tolDCs) with powerful therapeutic potential has been well - established to combat autoimmune responses in laboratory models and early clinical trials. In contrast to in vitro tolDCs induction, in vivo elicitation by specifically targeting multiple cell - surface receptors has shown greater promise with more advantages. Here, we summarize the role of DCs in governing immune tolerance and in the process of initiating and perpetuating MS. We then highlight the most promising cell-surface receptors expressed on DCs currently being explored as the viable pharmacological targets through antigen delivery to generate tolDCs in vivo, to guide feasible immunotherapeutic strategies.

Abstract Background The production of succinic acid (SA) from biomass has attracted worldwide interest. Saccharomyces cerevisiae is preferred for SA production due to its strong tolerance to low pH conditions, ease of genetic manipulation, and extensive application in industrial processes. However, when compared with bacterial producers, the SA titers and productivities achieved by engineered S. cerevisiae strains were relatively low. To develop efficient SA-producing strains, it’s necessary to clearly understand how S. cerevisiae cells respond to SA. Results In this study, we cultivated five S. cerevisiae strains with different genetic backgrounds under different concentrations of SA. Among them, KF7 and NBRC1958 demonstrated high tolerance to SA, whereas NBRC2018 displayed the least tolerance. Therefore, these three strains were chosen to study how S. cerevisiae responds to SA. Under a concentration of 20 g/L SA, only a few differentially expressed genes were observed in three strains. At the higher concentration of 60 g/L SA, the response mechanisms of the three strains diverged notably. For KF7, genes involved in the glyoxylate cycle were significantly downregulated, whereas genes involved in gluconeogenesis, the pentose phosphate pathway, protein folding, and meiosis were significantly upregulated. For NBRC1958, genes related to the biosynthesis of vitamin B6, thiamin, and purine were significantly downregulated, whereas genes related to protein folding, toxin efflux, and cell wall remodeling were significantly upregulated. For NBRC2018, there was a significant upregulation of genes connected to the pentose phosphate pathway, gluconeogenesis, fatty acid utilization, and protein folding, except for the small heat shock protein gene HSP26. Overexpression of HSP26 and HSP42 notably enhanced the cell growth of NBRC1958 both in the presence and absence of SA. Conclusions The inherent activities of small heat shock proteins, the levels of acetyl-CoA and the strains’ potential capacity to consume SA all seem to affect the responses and tolerances of S. cerevisiae strains to SA. These factors should be taken into consideration when choosing host strains for SA production. This study provides a theoretical basis and identifies potential host strains for the development of robust and efficient SA-producing strains.

Abstract Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world. Triticum timopheevii (2n = 4x = 28) is an allotetraploid wheat wild relative species containing the At and G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly of T. timopheevii accession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb and included the mitochondrial and plastid genome sequences. Genome annotation predicted 166,325 gene models including 70,365 genes with high confidence. DNA methylation analysis showed that the G genome had on average more methylated bases than the At genome. In summary, the T. timopheevii genome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.

Abstract Breast cancer (BC) is a multifaceted disease characterized by distinct molecular subtypes and varying responses to treatment. In BC, the phosphatidylinositol 3-kinase (PI3K) pathway has emerged as a crucial contributor to the development, advancement, and resistance to treatment. This review article explores the implications of the PI3K pathway in predictive, preventive, and personalized medicine for BC. It emphasizes the identification of predictive biomarkers, such as PIK3CA mutations, and the utility of molecular profiling in guiding treatment decisions. The review also discusses the potential of targeting the PI3K pathway for preventive strategies and the customization of therapy based on tumor stage, molecular subtypes, and genetic alterations. Overcoming resistance to PI3K inhibitors and exploring combination therapies are addressed as important considerations. While this field holds promise in improving patient outcomes, further research and clinical trials are needed to validate these approaches and translate them into clinical practice. Graphical Abstract

Summary: This review explores the hallmarks of cancer resistance, including drug efflux mediated by ATP-binding cassette (ABC) transporters, metabolic reprogramming characterized by the Warburg effect, and the dynamic interplay between cancer cells and mitochondria. The role of cancer stem cells (CSCs) in treatment resistance and the regulatory influence of non-coding RNAs, such as long non-coding RNAs (lncRNAs), microRNAs (miRNAs), and circular RNAs (circRNAs), are studied. The chapter emphasizes future directions, encompassing advancements in immunotherapy, strategies to counter adaptive resistance, integration of artificial intelligence for predictive modeling, and the identification of biomarkers for personalized treatment. The comprehensive exploration of these hallmarks provides a foundation for innovative therapeutic approaches, aiming to navigate the complex landscape of cancer resistance and enhance patient outcomes.

The rise of antimicrobial resistance in ESKAPEE pathogens poses significant clinical challenges, especially in polymicrobial infections. Bacteriophage-derived endolysins offer promise in combating this crisis, but face practical hurdles. Our study focuses on engineering endolysins from a Klebsiella pneumoniae phage, fusing them with ApoE23 and COG133 peptides. We assessed the resulting chimeric proteins’ bactericidal activity against ESKAPEE pathogens in vitro. ApoE23-Kp84B (CHU-1) reduced over 3 log units of CFU for A. baumannii, E. faecalis, K. pneumoniae within 1 h, while COG133-Kp84B (CHU-2) showed significant efficacy against S. aureus. COG133-L1-Kp84B, with a GS linker insertion in CHU-2, exhibited outstanding bactericidal activity against E. cloacae and P. aeruginosa. Scanning electron microscopy revealed alterations in bacterial morphology after treatment with engineered endolysins. Notably, CHU-1 demonstrated promising anti-biofilm and anti-persister cell activity against A. baumannii and E. faecalis but had limited efficacy in a bacteremia mouse model of their coinfection. Our findings advance the field of endolysin engineering, facilitating the customization of these proteins to target specific bacterial pathogens. This approach holds promise for the development of personalized therapies tailored to combat ESKAPEE infections effectively.

BackgroundThe house dust mite (HDM) is widely recognized as the most prevalent allergen in allergic diseases. Allergen-specific immunotherapy (AIT) has been successfully implemented in clinical treatment for HDM. Hypoallergenic B-cell epitope-based vaccine designed by artificial intelligence (AI) represents a significant progression of recombinant hypoallergenic allergen derivatives.MethodThe three-dimensional protein structure of Der f 36 was constructed using Alphafold2. AI-based tools were employed to predict B-cell epitopes, which were subsequently verified through IgE-reaction testing. Hypoallergenic Der f 36 was then synthesized, expressed, and purified. The reduced allergenicity was assessed by enzyme-linked immunosorbent assay (ELISA), immunoblotting, and basophil activation test. T-cell response to hypoallergenic Der f 36 and Der f 36 was evaluated based on cytokine expression in the peripheral blood mononuclear cells (PBMCs) of patients. The immunogenicity was evaluated and compared through rabbit immunization with hypoallergenic Der f 36 and Der f 36, respectively. The inhibitory effect of the blocking IgG antibody on the specific IgE-binding activity and basophil activation of Der f 36 allergen was also examined.ResultsThe final selected non-allergic B-cell epitopes were 25–48, 57–67, 107–112, 142–151, and 176–184. Hypoallergenic Der f 36 showed significant reduction in IgE-binding activity. The competitive inhibition of IgE-binding to Der f 36 was investigated using the hypoallergenic Der f 36, and only 20% inhibition could be achieved, which is greatly reduced when compared with inhibition by Der f 36 (98%). The hypoallergenic Der f 36 exhibited a low basophil-stimulating ratio similar to that of the negative control, and it could induce an increasing level of IFN‐γ but not Th2 cytokines IL-5 and IL-13 in PBMCs. The vaccine-specific rabbit blocking IgG antibodies could inhibit the patients’ IgE binding and basophil stimulation activity of Derf 36.ConclusionThis study represents the first application of an AI strategy to facilitate the development of a B-cell epitope-based hypoallergenic Der f 36 vaccine, which may become a promising immunotherapy for HDM-allergic patients due to its reduced allergenicity and its high immunogenicity in inducing blocking of IgG.

In the process of synaptic formation, neurons must not only adhere to specific principles when selecting synaptic partners but also possess mechanisms to avoid undesirable connections. Yet, the strategies employed to prevent unwarranted associations have remained largely unknown. In our study, we have identified the pivotal role of combinatorial clustered protocadherin gamma (γ-PCDH) expression in orchestrating synaptic connectivity in the mouse neocortex. Through 5' end single-cell sequencing, we unveiled the intricate combinatorial expression patterns of γ-PCDH variable isoforms within neocortical neurons. Furthermore, our whole-cell patch-clamp recordings demonstrated that as the similarity in this combinatorial pattern among neurons increased, their synaptic connectivity decreased. Our findings elucidate a sophisticated molecular mechanism governing the construction of neural networks in the mouse neocortex.

Summary: LMNA gene mutation can cause muscular dystrophy, and post-translational modification plays a critical role in regulating its function. Here, we identify that lamin A is palmitoylated at cysteine 522, 588, and 591 residues, which are reversely catalyzed by palmitoyltransferase zinc finger DHHC-type palmitoyltransferase 5 (ZDHHC5) and depalmitoylase α/β hydrolase domain 7 (ABHD7). Furthermore, the metabolite lactate promotes palmitoylation of lamin A by inhibiting the interaction between it and ABHD7. Interestingly, low-level palmitoylation of lamin A promotes, whereas high-level palmitoylation of lamin A inhibits, murine myoblast differentiation. Together, these observations suggest that ABHD7-mediated depalmitoylation of lamin A controls myoblast differentiation.