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关键词： acetate   bleeding   canine   cardiac output   vasodilation  

摘要： To compare macrocirculatory effects of haemorrhage followed by fluid resuscitation with Plasma-Lyte A (PA) or Ringer’s Lactate (RL) crystalloid solution in dogs under sevoflurane anaesthesia.

关键词： Kirigami Metamaterials   Negative Poisson's ratio   Anti-chiral   Out-of-plane buckling   High-fidelity display  

摘要： Auxetic Kirigami Metamaterials (KMs) offer effective negative Poisson's ratios under large stretching and hold promise for next-generation flexible metastructures. However, most existing designs suffer from either pronounced out-of-plane buckling or limited ability to maintain desirable auxetic behavior under large stretching. This study proposes a novel anti-chiral auxetic KM architecture employing an L-shaped cut configuration that concurrently exhibits mirror symmetry within the unit cell and fourfold rotational symmetry in each quadratic domain, thereby enabling the same mechanical response in the horizontal and vertical directions. Through systematic parametric optimization, the designed KM attains a consistently near-ideal Poisson's ratio of - 1 under uniaxial stretching up to 40%. Their large deformations rely predominantly on in-plane bending of the connecting ligaments, effectively suppressing out-of-plane buckling even at large strains, which is a capability rarely achieved in previous Kirigami systems. Leveraging this characteristic, we further demonstrate high-fidelity display functionality using a fluorescent '' pattern that retains its geometric fidelity throughout stretching. These results establish anti-chiral KMs as a lightweight, mechanically robust, and buckling-resistant platform, providing a new structural paradigm for applications such as flexible electronics and deformable displays.

关键词： Monoclonal antibodies   Chromatography   Host cell proteins   Acyl-protein thioesterase-1   Protein-protein interactions   Biolayer interferometry  

摘要： Difficult-to-remove host cell proteins (HCPs) can compromise monoclonal antibody (mAb) product quality and stability. This study investigated the persistence of acyl-protein thioesterase-1, a polysorbate-degrading HCP, during downstream processing and its interaction with a set of mAbs. Acyl-protein thioesterase-1 remained in the eluates after reprocessing a specific mAb with protein A affinity liquid chromatography, even when various wash buffer additives were used, indicating a strong product:HCP interaction that resists conventional purification strategies. Upon cleaving the mAb and purifying its Fab and Fc fragments, we used biolayer interferometry to show that acyl-protein thioesterase-1 selectively and tightly binds to the Fab region. Domain-specific sensor-immobilization approach suggested that the binding site was located on the antibody's CH1 domain, and the interaction was influenced by preincubation with the mAb's cognate antigen. These findings highlight the importance of characterizing HCP:mAb interactions as a basis for improving HCP reduction strategies.

关键词： LINE-1   逆转录转座子   肿瘤   基因组不稳定性   表观遗传调控  

摘要： 转座子又称跳跃基因,是一段能够在染色体内或不同染色体之间改变自身位置的DNA序列。长散在核元件-1(long interspersed element 1,LINE-1)作为人类基因组中唯一具有自主逆转座活性的转座子,其动态调控对维持基因组稳定性具有重要的意义。在正常生理状态下,宿主通过表观遗传等机制使LINE-1处于沉默状态,但当这种精密调控被打破时,LINE-1异常激活介导的插入突变会引发基因组不稳定,进而诱发多种遗传性疾病和恶性肿瘤。近年来的研究证据表明,在乳腺癌、食管癌、肺癌以及结直肠癌等多种肿瘤中存在LINE-1的高表达,提示LINE-1的异常激活与肿瘤发生发展存在密切关联。本文综述了宿主对LINE-1多层次的调控网络,包括表观遗传修饰、非编码RNA以及多种宿主限制因子;探讨了LINE-1在肿瘤微环境中异常激活的分子机制,并总结了LINE-1影响肿瘤发生发展的多种途径,例如影响基因组稳定性、引发炎症和免疫反应以及参与细胞永生化过程。本文不仅为LINE-1作为肿瘤分子诊断标志物提供了理论依据,同时为基于LINE-1调控的新型抗肿瘤治疗策略提供了新的视角。

关键词： Clinic assessment   Type 1 diabetes   Health systems   Global health   Research preparedness  

摘要： Type 1 diabetes (T1D) incidence is rising globally, particularly in low- and middle-income countries (LMICs) that face major gaps in access and treatment and high levels of preventable mortality. We developed READY-T1D (Research and Service Delivery Readiness in Type 1 Diabetes) to assess service provision and research preparedness in clinics providing T1D services to children and adolescents as part of the Global Collaborative for Changing Diabetes in Children (GC-CDiC).

关键词： double-stranded RNA (dsRNA)   RNA structure   oligoadenylate synthetase   innate immunity   antiviral  

摘要： The innate immune system relies on pathogen recognition receptors, such as the 2′,5′-oligoadenylate synthetase (OAS) proteins, to detect pathogen-associated molecular patterns like viral double-stranded (ds)RNA. A specific splicing variant of OAS1 (OAS1-p46) has been implicated in initiating an immune response that leads to decreased disease severity during SARS-CoV-2 infection. OAS1-p46 has a C-terminal lipid modification motif that allows for anchoring of the protein to intracellular membranes and thus potential colocalization with immunogenic viral RNA regions such as the SARS-CoV-2 5′-untranslated region (5′-UTR). Here, we show that OAS proteins can detect the 5′-structured elements (5′-SE)–comprising the 5′-UTR and three additional stem-loop structures–and activate the cellular RNase L pathway. Through systematic 3′-end truncations of the 5′-SE, we show that the smallest 5′-SE fragment capable of potently activating OAS1 is the conserved and highly structured SL1-4b region, containing the first four stem-loop structures and their intervening linking sequences (SL1-4), as well as an unstructured region (“SL4b”) to the 3′-side of SL4. Analyses of OAS1 activation and RNA secondary structure probing using selective 2′-hydroxyl acylation analyzed by primer extension and mutational profiling (SHAPE-MaP) of additional SL1-4b RNA variants suggests a model in which SL4 acts as the primary OAS1 interaction site, while the unstructured SL4b region and two other stem-loops (SL1 and SL3) are necessary for optimal presentation of this region for OAS1 activation. Our findings reveal a structurally complex viral RNA region that potently activates OAS1, underscoring the potential complexity of RNAs that can strongly activate this innate immune sensor.

关键词： androgenic alopecia   glucagon-like peptide 1 agonist   hair loss   obesity   telogen effluvium   type II diabetes  

关键词： Sein   Tumeurs fibro-épithéliales   Tumeurs phyllodes   Tumeurs phyllodes malignes   Breast   Fibroepithelial tumours   Phyllodes tumours   Malignant phyllodes tumours  

摘要： Les tumeurs phyllodes sont des tumeurs rares du sein (0,3 à 1 % des tumeurs mammaires). Il s’agit de lésions fibro-épithéliales qui peuvent être bénigne, borderline ou maligne. La majorité des tumeurs phyllodes sont des tumeurs phyllodes bénignes (60 à 75 %). Les critères diagnostiques des tumeurs phyllodes malignes sont relativement bien définis par l’OMS 2019. Le diagnostic de tumeur phyllode maligne est retenu en présence de territoires de différenciation sarcomateuse hétérologue (hors liposarcome bien différencié) ou en présence concomitante des cinq critères péjoratifs suivants : pléomorphisme nucléaire marqué, plage stromale pure au grossissement ×40 (objectif ×4 et grossissement ×10 des oculaires), index mitotique élevé (≥ 5 mitoses/mm² ; ≥ 10 mitoses/10 HPF), hypercellularité diffuse et mauvaise limitation. La tumeur phyllode bénigne ne présente aucun des cinq critères péjoratifs précédemment énumérés. Les tumeurs phyllodes borderline correspondent aux tumeurs phyllodes qui n’entrent pas dans les critères diagnostiques des tumeurs phyllodes bénignes et malignes. Les métastases à distances apparaissent dans les cinq à huit ans après le diagnostic de tumeur phyllode. Elles concernent 16 % des tumeurs phyllodes malignes. C’est alors la composante stromale qui est retrouvée au site métastatique, qui sera volontiers le poumon, l’os ou le cœur. Le respect strict des critères de grading de la classification OMS 2019 ne permet pas de prédire avec certitude le risque de rechute métastatique. En particulier, la nécessité d’avoir les cinq critères péjoratifs concomitants. Plusieurs travaux ont récemment remis en cause cette notion et proposent de nouveaux critères diagnostiques qui nécessiteraient cependant d’être validés dans des études prospectives pour être utilisés.

关键词： Osteoarthritis   primary biliary cholangitis   ursodeoxycholic acid   farnesoid X receptor   glucagon-like peptide-1 receptor agonist   Clostridium bolteae  

摘要： Introduction Although previous research has demonstrated the functional roles of gut microbiota-derived metabolites in systematic immune and metabolic disorders, few studies have explored the possible actions of these metabolites in conditions with localized effects, such as joint diseases. Osteoarthritis, a prevalent localized joint disease often referred to as "wear and tear" arthritis, affects more than 595 million people worldwide. Nevertheless, its underlying mechanism is not fully understood, and no disease-modifying drugs are available. Understanding the disease mechanisms of osteoarthritis and developing mechanism-based therapeutic approaches is an urgent yet unmet clinical need. Gut microbiota dysbiosis and several microbial metabolites have been implicated in osteoarthritis;however, whether a functional gut-joint axis exists has yet to be established. Rationale Bile acids, an important and abundant class of microbial metabolites, act as signaling molecules through receptors, such as farnesoid X receptor (FXR). FXR inhibition in L cells stimulates glucagon-like peptide 1 (GLP-1) production and secretion, and GLP-1 receptor (GLP-1R) agonists show anti-cartilage degrading effects in osteoarthritis, which suggests that GLP-1 is a potential mediator linking the intestine and the joint. These findings raise the possibility of a functional and targetable gut-joint axis. Given that bile acid receptors are promising targets with several available US Food and Drug Administration (FDA)-approved drugs, understanding the importance of bile acid metabolism and signaling and its relevance to osteoarthritis may offer previously unrealized translational opportunities. Results Through targeted metabolomics analysis of two independent cohorts totaling 1868 individuals, we identified alterations in bile acid metabolism with reduced levels of glycoursodeoxycholic acid (GUDCA) in osteoarthritis patients compared with controls. Similar patterns were observed when correlating red