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Structural and functional insights into the C-terminal signal domain of the Bacteroidetes type-IX secretion system. 类杆菌 IX 型分泌系统 C 端信号域的结构和功能研究。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230448
Danuta Mizgalska, Arturo Rodríguez-Banqueri, Florian Veillard, Mirosław Książęk, Theodoros Goulas, Tibisay Guevara, Ulrich Eckhard, Jan Potempa, F Xavier Gomis-Rüth

Gram-negative bacteria from the Bacteroidota phylum possess a type-IX secretion system (T9SS) for protein secretion, which requires cargoes to have a C-terminal domain (CTD). Structurally analysed CTDs are from Porphyromonas gingivalis proteins RgpB, HBP35, PorU and PorZ, which share a compact immunoglobulin-like antiparallel 3+4 β-sandwich (β1-β7). This architecture is essential as a P. gingivalis strain with a single-point mutant of RgpB disrupting the interaction of the CTD with its preceding domain prevented secretion of the protein. Next, we identified the C-terminus ('motif C-t.') and the loop connecting strands β3 and β4 ('motif Lβ3β4') as conserved. We generated two strains with insertion and replacement mutants of PorU, as well as three strains with ablation and point mutants of RgpB, which revealed both motifs to be relevant for T9SS function. Furthermore, we determined the crystal structure of the CTD of mirolase, a cargo of the Tannerella forsythia T9SS, which shares the same general topology as in Porphyromonas CTDs. However, motif Lβ3β4 was not conserved. Consistently, P. gingivalis could not properly secrete a chimaeric protein with the CTD of peptidylarginine deiminase replaced with this foreign CTD. Thus, the incompatibility of the CTDs between these species prevents potential interference between their T9SSs.

细菌门的革兰氏阴性细菌拥有一种用于分泌蛋白质的 IX 型分泌系统(T9SS),该系统要求货物具有一个 C 端结构域(CTD)。对牙龈卟啉单胞菌蛋白 RgpB、HBP35、PorU 和 PorZ 的 CTD 进行了结构分析,它们共享一个紧凑的免疫球蛋白样反平行 3+4 β-三明治(β1-β7)。这种结构非常重要,因为一株牙龈脓疱病菌的 RgpB 单点突变体破坏了 CTD 与其前端结构域的相互作用,从而阻止了蛋白质的分泌。接下来,我们确定了 C 端("motif C-t.")和连接 β3 和 β4 链的环路("motif Lβ3β4")是保守的。我们生成了两株 PorU 的插入突变体和置换突变体,以及三株 RgpB 的消融突变体和点突变体,结果表明这两个图案与 T9SS 的功能有关。此外,我们还测定了连翘丹菌 T9SS 的载体 mirolase CTD 的晶体结构,该结构与卟啉单胞菌 CTD 的一般拓扑结构相同。然而,图案 Lβ3β4 并不保守。同样,牙龈卟啉菌不能正常分泌肽精氨酸脱氨酶 CTD 被这种外来 CTD 取代的嵌合蛋白。因此,这些物种之间 CTD 的不兼容性阻止了它们的 T9SS 之间的潜在干扰。
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引用次数: 0
MYH7 R453C induced cardiac remodelling via activating TGF-β/Smad2/3, ERK1/2 and Nox4/ROS/NF-κB signalling pathways. MYH7 R453C通过激活TGF-β/Smad2/3、ERK1/2和Nox4/ROS/NF-κB信号通路诱导心脏重塑。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230427
Lingyu Wang, Linquan Li, Dazhong Zhao, Hongming Yuan, Huanyu Zhang, Jiahuan Chen, Daxin Pang, Yi Lu, Hongsheng Ouyang

Hypertrophic cardiomyopathy (HCM) is a monogenic cardiac disorder commonly induced by sarcomere gene mutations. However, the mechanism for HCM is not well defined. Here, we generated transgenic MYH7 R453C and MYH6 R453C piglets and found both developed typical cardiac hypertrophy. Unexpectedly, we found serious fibrosis and cardiomyocyte loss in the ventricular of MYH7 R453C, not MYH6 R453C piglets, similar to HCM patients. Then, RNA-seq analysis and western blotting identified the activation of ERK1/2 and PI3K-Akt pathways in MYH7 R453C. Moreover, we observed an increased expression of fetal genes and an excess of reactive oxygen species (ROS) in MYH7 R453C piglet models, which was produced by Nox4 and subsequently induced inflammatory response. Additionally, the phosphorylation levels of Smad2/3, ERK1/2 and NF-kB p65 proteins were elevated in cardiomyocytes with the MYH7 R453C mutation. Furthermore, epigallocatechin gallate, a natural bioactive compound, could be used as a drug to reduce cell death by adjusting significant downregulation of the protein expression of Bax and upregulated Bcl-2 levels in the H9C2 models with MYH7 R453C mutation. In conclusion, our study illustrated that TGF-β/Smad2/3, ERK1/2 and Nox4/ROS pathways have synergistic effects on cardiac remodelling and inflammation in MYH7 R453C mutation.

肥厚型心肌病(HCM)是一种单基因心脏疾病,通常由肌节基因突变诱发。然而,HCM 的发病机制尚未明确。在这里,我们生成了转基因 MYH7 R453C 和 MYH6 R453C 仔猪,发现它们都出现了典型的心脏肥大。出乎意料的是,我们发现 MYH7 R453C 仔猪的心室出现了严重的纤维化和心肌细胞丢失,而 MYH6 R453C 仔猪则没有,这与 HCM 患者相似。然后,RNA-seq 分析和 Western 印迹确定了 MYH7 R453C 中 ERK1/2 和 PI3K-Akt 通路的激活。此外,我们还观察到在 MYH7 R453C 小猪模型中胎儿基因表达增加,活性氧(ROS)过量,由 Nox4 产生,随后诱发炎症反应。此外,MYH7 R453C 突变的心肌细胞中 Smad2/3、ERK1/2 和 NF-kB p65 蛋白的磷酸化水平升高。此外,表没食子儿茶素没食子酸酯作为一种天然生物活性化合物,可通过调节MYH7 R453C突变的H9C2模型中Bax蛋白表达的显著下调和Bcl-2水平的上调来减少细胞死亡。总之,我们的研究表明,TGF-β/Smad2/3、ERK1/2和Nox4/ROS通路对MYH7 R453C突变的心脏重塑和炎症具有协同作用。
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引用次数: 0
Amyloidogenic regions in beta-strands II and III modulate the aggregation and toxicity of SOD1 in living cells. 贝塔链 II 和 III 中的淀粉样蛋白生成区可调节 SOD1 在活细胞中的聚集和毒性。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-05 DOI: 10.1098/rsob.230418
Luke McAlary, Jeremy R Nan, Clay Shyu, Mine Sher, Steven S Plotkin, Neil R Cashman

Mutations in the protein superoxide dismutase-1 (SOD1) promote its misfolding and aggregation, ultimately causing familial forms of the debilitating neurodegenerative disease amyotrophic lateral sclerosis (ALS). Currently, over 220 (mostly missense) ALS-causing mutations in the SOD1 protein have been identified, indicating that common structural features are responsible for aggregation and toxicity. Using in silico tools, we predicted amyloidogenic regions in the ALS-associated SOD1-G85R mutant, finding seven regions throughout the structure. Introduction of proline residues into β-strands II (I18P) or III (I35P) reduced the aggregation propensity and toxicity of SOD1-G85R in cells, significantly more so than proline mutations in other amyloidogenic regions. The I18P and I35P mutations also reduced the capability of SOD1-G85R to template onto previously formed non-proline mutant SOD1 aggregates as measured by fluorescence recovery after photobleaching. Finally, we found that, while the I18P and I35P mutants are less structurally stable than SOD1-G85R, the proline mutants are less aggregation-prone during proteasome inhibition, and less toxic to cells overall. Our research highlights the importance of a previously underappreciated SOD1 amyloidogenic region in β-strand II (15QGIINF20) to the aggregation and toxicity of SOD1 in ALS mutants, and suggests that β-strands II and III may be good targets for the development of SOD1-associated ALS therapies.

超氧化物歧化酶-1(SOD1)蛋白的突变会促进其错误折叠和聚集,最终导致家族性神经退行性疾病肌萎缩性脊髓侧索硬化症(ALS)。目前,在 SOD1 蛋白中发现了 220 多种导致 ALS 的突变(大部分是错义突变),这表明共同的结构特征是导致聚集和毒性的原因。我们利用硅学工具预测了与 ALS 相关的 SOD1-G85R 突变体中的淀粉样蛋白生成区域,发现整个结构中有七个区域。在β链II(I18P)或III(I35P)中引入脯氨酸残基可降低SOD1-G85R在细胞中的聚集倾向和毒性,其效果明显优于其他淀粉样变性区域的脯氨酸突变。I18P 和 I35P 突变还降低了 SOD1-G85R 在先前形成的非脯氨酸突变 SOD1 聚集体上的模板能力,这是用光漂白后的荧光恢复来测量的。最后,我们发现,虽然 I18P 和 I35P 突变体的结构稳定性不如 SOD1-G85R,但脯氨酸突变体在蛋白酶体抑制过程中不易发生聚集,而且总体上对细胞的毒性较低。我们的研究强调了以前未被重视的 SOD1 β 链 II(15QGIINF20)淀粉样蛋白生成区对 SOD1 在 ALS 突变体中的聚集和毒性的重要性,并表明 β 链 II 和 III 可能是开发 SOD1 相关 ALS 疗法的良好靶点。
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引用次数: 0
Effective training of nanopore callers for epigenetic marks with limited labelled data. 利用有限的标记数据对纳米孔调用仪进行表观遗传标记的有效训练。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.230449
Brian Yao, Chloe Hsu, Gal Goldner, Yael Michaeli, Yuval Ebenstein, Jennifer Listgarten

Nanopore sequencing platforms combined with supervised machine learning (ML) have been effective at detecting base modifications in DNA such as 5-methylcytosine (5mC) and N6-methyladenine (6mA). These ML-based nanopore callers have typically been trained on data that span all modifications on all possible DNA [Formula: see text]-mer backgrounds-a complete training dataset. However, as nanopore technology is pushed to more and more epigenetic modifications, such complete training data will not be feasible to obtain. Nanopore calling has historically been performed with hidden Markov models (HMMs) that cannot make successful calls for [Formula: see text]-mer contexts not seen during training because of their independent emission distributions. However, deep neural networks (DNNs), which share parameters across contexts, are increasingly being used as callers, often outperforming their HMM cousins. It stands to reason that a DNN approach should be able to better generalize to unseen [Formula: see text]-mer contexts. Indeed, herein we demonstrate that a common DNN approach (DeepSignal) outperforms a common HMM approach (Nanopolish) in the incomplete data setting. Furthermore, we propose a novel hybrid HMM-DNN approach, amortized-HMM, that outperforms both the pure HMM and DNN approaches on 5mC calling when the training data are incomplete. This type of approach is expected to be useful for calling other base modifications such as 5-hydroxymethylcytosine and for the simultaneous calling of different modifications, settings in which complete training data are not likely to be available.

纳米孔测序平台与有监督的机器学习(ML)相结合,可有效检测 DNA 中的碱基修饰,如 5-甲基胞嘧啶(5mC)和 N6-甲基腺嘌呤(6mA)。这些基于 ML 的纳米孔呼叫器通常是在涵盖所有可能的 DNA [公式:见正文]-聚合物背景上的所有修饰的数据--一个完整的训练数据集上进行训练的。然而,随着纳米孔技术被推向越来越多的表观遗传修饰,这种完整的训练数据将难以获得。纳米孔调用历来使用隐马尔可夫模型(HMMs),由于其独立的发射分布,HMMs 无法成功调用训练期间未见的[公式:见正文]-mer 背景。然而,深度神经网络(DNN)在不同语境中共享参数,正越来越多地被用作调用器,其性能往往优于 HMM。按理说,DNN 方法应该能够更好地泛化到未见[公式:见正文]的语境中。事实上,我们在本文中证明,在不完整数据环境中,常见的 DNN 方法(DeepSignal)优于常见的 HMM 方法(Nanopolish)。此外,我们还提出了一种新颖的 HMM-DNN 混合方法(amortized-HMM),在训练数据不完整的情况下,该方法在 5mC 调用方面的表现优于纯 HMM 和 DNN 方法。这种方法有望用于调用其他碱基修饰,如 5-hydroxymethylcytosine 以及同时调用不同的修饰,因为在这种情况下不可能获得完整的训练数据。
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引用次数: 0
Altered socio-affective communication and amygdala development in mice with protocadherin10-deficient interneurons. 原粘连蛋白10缺陷中间神经元小鼠的社会情感交流和杏仁核发育发生改变
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-19 DOI: 10.1098/rsob.240113
Tania Aerts, Anneleen Boonen, Lieve Geenen, Anne Stulens, Luca Masin, Anna Pancho, Annick Francis, Elise Pepermans, Geert Baggerman, Frans Van Roy, Markus Wöhr, Eve Seuntjens

Autism spectrum disorder (ASD) is a group of neurodevelopmental conditions associated with deficits in social interaction and communication, together with repetitive behaviours. The cell adhesion molecule protocadherin10 (PCDH10) is linked to ASD in humans. Pcdh10 is expressed in the nervous system during embryonic and early postnatal development and is important for neural circuit formation. In mice, strong expression of Pcdh10 in the ganglionic eminences and in the basolateral complex (BLC) of the amygdala was observed at mid and late embryonic stages, respectively. Both inhibitory and excitatory neurons expressed Pcdh10 in the BLC at perinatal stages and vocalization-related genes were enriched in Pcdh10-expressing neurons in adult mice. An epitope-tagged Pcdh10-HAV5 mouse line revealed endogenous interactions of PCDH10 with synaptic proteins in the young postnatal telencephalon. Nuanced socio-affective communication changes in call emission rates, acoustic features and call subtype clustering were primarily observed in heterozygous pups of a conditional knockout (cKO) with selective deletion of Pcdh10 in Gsh2-lineage interneurons. These changes were less prominent in heterozygous ubiquitous Pcdh10 KO pups, suggesting that altered anxiety levels associated with Gsh2-lineage interneuron functioning might drive the behavioural effects. Together, loss of Pcdh10 specifically in interneurons contributes to behavioural alterations in socio-affective communication with relevance to ASD.

自闭症谱系障碍(ASD)是一组与社交互动和沟通障碍以及重复行为有关的神经发育疾病。细胞粘附分子原粘连蛋白10(PCDH10)与人类自闭症谱系障碍有关。Pcdh10 在胚胎和出生后早期发育过程中在神经系统中表达,对神经回路的形成非常重要。在小鼠胚胎发育中期和晚期,分别在神经节突起和杏仁核基底复合体(BLC)中观察到 Pcdh10 的强表达。在围产期,抑制性神经元和兴奋性神经元都在BLC中表达Pcdh10,成年小鼠的Pcdh10表达神经元中富含发声相关基因。表位标记的Pcdh10-HAV5小鼠品系揭示了PCDH10与出生后幼年端脑中突触蛋白的内源性相互作用。在Gsh2线型中间神经元中选择性缺失Pcdh10的条件性基因敲除(cKO)杂合子幼鼠中,主要观察到了叫声发射率、声学特征和叫声亚型集群方面的细微社会情感交流变化。这些变化在杂合泛在 Pcdh10 KO 幼鼠中并不那么突出,这表明与 Gsh2 线型中间神经元功能相关的焦虑水平的改变可能会驱动行为效应。总之,Pcdh10在中间神经元中的特异性缺失导致了与自闭症相关的社会情感交流的行为改变。
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引用次数: 0
Beyond amyloid and tau: rethinking Alzheimer's disease through less explored avenues. 超越淀粉样蛋白和 tau:通过较少探索的途径重新思考阿尔茨海默病。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.240035
M Gyimesi, R K Okolicsanyi, L M Haupt

Neurodegenerative diseases, particularly Alzheimer's disease (AD), pose a significant challenge in ageing populations. Our current understanding indicates that the onset of toxic amyloid and tau protein pathologies initiates disease progression. However, existing treatments targeting these hallmark symptoms offer symptomatic relief without halting disease advancement. This review offers an alternative perspective on AD, centring on impaired adult hippocampal neurogenesis (AHN) as a potential early aetiological factor. By delving into the intricate molecular events during the initial stages of AD (Braak Stages I-III), a novel hypothesis is presented, interweaving the roles of Notch signalling and heparan sulfate proteoglycans (HSPGs) in compromised AHN. While acknowledging the significance of the amyloid and tau hypotheses, it calls for further exploration beyond these paradigms, suggesting the potential of altered HS sulfation patterns in AD initiation. Future directions propose more detailed investigations into early HS aggregation, aberrant sulfation patterns and examination of their temporal relationship with tau hyperphosphorylation. In challenging the conventional 'triggers' of AD and urging their reconsideration as symptoms, this review advocates an alternative approach to understanding this disease, offering new avenues of investigation into the intricacies of AD pathogenesis.

神经退行性疾病,尤其是阿尔茨海默病(AD),给老龄人口带来了巨大挑战。我们目前的认识表明,淀粉样蛋白和 tau 蛋白的毒性病理变化是疾病进展的起因。然而,针对这些标志性症状的现有治疗方法只能缓解症状,却无法阻止疾病的发展。这篇综述从另一个角度探讨了注意力缺失症,将受损的成人海马神经元生成(AHN)作为潜在的早期致病因素。通过深入研究 AD 初期阶段(Braak 阶段 I-III)错综复杂的分子事件,本文提出了一个新的假设,将 Notch 信号和硫酸肝素蛋白多糖(HSPGs)在受损的 AHN 中的作用交织在一起。在承认淀粉样蛋白假说和 tau 假说的重要性的同时,该假说要求进一步探索这些假说之外的其他假说,并提出了在 AD 发病过程中改变 HS 硫酸化模式的可能性。未来的研究方向是对早期HS聚集、异常硫酸化模式进行更详细的调查,并研究它们与tau过度磷酸化的时间关系。这篇综述对AD的传统 "诱发因素 "提出了质疑,并敦促人们重新考虑它们作为症状的作用,它提倡用另一种方法来理解这种疾病,为研究AD发病机制的复杂性提供了新的途径。
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引用次数: 0
Kinetoplastid kinetochore proteins KKT14-KKT15 are divergent Bub1/BubR1-Bub3 proteins. 细胞核动点蛋白 KKT14-KKT15 是不同的 Bub1/BubR1-Bub3 蛋白。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-12 DOI: 10.1098/rsob.240025
Daniel Ballmer, William Carter, Jolien J E van Hooff, Eelco C Tromer, Midori Ishii, Patryk Ludzia, Bungo Akiyoshi

Faithful transmission of genetic material is crucial for the survival of all organisms. In many eukaryotes, a feedback control mechanism called the spindle checkpoint ensures chromosome segregation fidelity by delaying cell cycle progression until all chromosomes achieve proper attachment to the mitotic spindle. Kinetochores are the macromolecular complexes that act as the interface between chromosomes and spindle microtubules. While most eukaryotes have canonical kinetochore proteins that are widely conserved, kinetoplastids such as Trypanosoma brucei have a seemingly unique set of kinetochore proteins including KKT1-25. It remains poorly understood how kinetoplastids regulate cell cycle progression or ensure chromosome segregation fidelity. Here, we report a crystal structure of the C-terminal domain of KKT14 from Apiculatamorpha spiralis and uncover that it is a pseudokinase. Its structure is most similar to the kinase domain of a spindle checkpoint protein Bub1. In addition, KKT14 has a putative ABBA motif that is present in Bub1 and its paralogue BubR1. We also find that the N-terminal part of KKT14 interacts with KKT15, whose WD40 repeat beta-propeller is phylogenetically closely related to a direct interactor of Bub1/BubR1 called Bub3. Our findings indicate that KKT14-KKT15 are divergent orthologues of Bub1/BubR1-Bub3, which promote accurate chromosome segregation in trypanosomes.

遗传物质的忠实传递对所有生物的生存都至关重要。在许多真核生物中,一种名为 "纺锤体检查点 "的反馈控制机制通过延迟细胞周期的进展来确保染色体分离的保真度,直到所有染色体都能正确附着到有丝分裂纺锤体上。动点是染色体与纺锤体微管之间的大分子复合体。虽然大多数真核生物都有广泛保守的典型动点核蛋白,但像布氏锥虫这样的动点细胞却有一套看似独特的动点核蛋白,其中包括 KKT1-25。人们对动点细胞如何调控细胞周期的进展或确保染色体分离的保真度仍然知之甚少。在这里,我们报告了螺旋拟尾柱虫 KKT14 C 端结构域的晶体结构,并发现它是一种伪激酶。它的结构与纺锤体检查点蛋白 Bub1 的激酶结构域最为相似。此外,KKT14还有一个假定的ABBA基序,存在于Bub1及其同源物BubR1中。我们还发现 KKT14 的 N 端部分与 KKT15 相互作用,而 KKT15 的 WD40 重复β-推进器在系统发育上与 Bub1/BubR1 的直接相互作用者 Bub3 关系密切。我们的研究结果表明,KKT14-KKT15是Bub1/BubR1-Bub3的不同直系同源物,而Bub1/BubR1-Bub3能促进锥虫染色体的准确分离。
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引用次数: 0
A pan-respiratory antiviral chemotype targeting a transient host multi-protein complex. 以瞬时宿主多蛋白复合物为目标的泛呼吸道抗病毒化学型。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-19 DOI: 10.1098/rsob.230363
Maya Michon, Andreas Müller-Schiffmann, Anuradha F Lingappa, Shao Feng Yu, Li Du, Fred Deiter, Sean Broce, Suguna Mallesh, Jackelyn Crabtree, Usha F Lingappa, Amanda Macieik, Lisa Müller, Philipp Niklas Ostermann, Marcel Andrée, Ortwin Adams, Heiner Schaal, Robert J Hogan, Ralph A Tripp, Umesh Appaiah, Sanjeev K Anand, Thomas W Campi, Michael J Ford, Jonathan C Reed, Jim Lin, Olayemi Akintunde, Kiel Copeland, Christine Nichols, Emma Petrouski, Ana R Moreira, I-Ting Jiang, Nicholas DeYarman, Ian Brown, Sharon Lau, Ilana Segal, Danielle Goldsmith, Shi Hong, Vinod Asundi, Erica M Briggs, Ngwe Sin Phyo, Markus Froehlich, Bruce Onisko, Kent Matlack, Debendranath Dey, Jaisri R Lingappa, Dharma M Prasad, Anatoliy Kitaygorodskyy, Dennis Solas, Homer Boushey, John Greenland, Satish Pillai, Michael K Lo, Joel M Montgomery, Christina F Spiropoulou, Carsten Korth, Suganya Selvarajah, Kumar Paulvannan, Vishwanath R Lingappa

We present a novel small molecule antiviral chemotype that was identified by an unconventional cell-free protein synthesis and assembly-based phenotypic screen for modulation of viral capsid assembly. Activity of PAV-431, a representative compound from the series, has been validated against infectious viruses in multiple cell culture models for all six families of viruses causing most respiratory diseases in humans. In animals, this chemotype has been demonstrated efficacious for porcine epidemic diarrhoea virus (a coronavirus) and respiratory syncytial virus (a paramyxovirus). PAV-431 is shown to bind to the protein 14-3-3, a known allosteric modulator. However, it only appears to target the small subset of 14-3-3 which is present in a dynamic multi-protein complex whose components include proteins implicated in viral life cycles and in innate immunity. The composition of this target multi-protein complex appears to be modified upon viral infection and largely restored by PAV-431 treatment. An advanced analog, PAV-104, is shown to be selective for the virally modified target, thereby avoiding host toxicity. Our findings suggest a new paradigm for understanding, and drugging, the host-virus interface, which leads to a new clinical therapeutic strategy for treatment of respiratory viral disease.

我们介绍了一种新型小分子抗病毒化学型,该化学型是通过非传统的无细胞蛋白质合成和组装表型筛选确定的,用于调节病毒的囊膜组装。该系列的代表性化合物 PAV-431 在多种细胞培养模型中针对传染性病毒的活性得到了验证,这些病毒包括引起人类大多数呼吸道疾病的所有六种病毒家族。在动物体内,该化学型已被证明对猪流行性腹泻病毒(一种冠状病毒)和呼吸道合胞病毒(一种副粘病毒)有效。PAV-431 可与蛋白质 14-3-3 结合,14-3-3 是一种已知的异位调节剂。不过,它似乎只针对 14-3-3 的一小部分,而 14-3-3 存在于一个动态的多蛋白复合物中,其成分包括与病毒生命周期和先天免疫有关的蛋白质。这种靶向多蛋白复合物的组成似乎会在病毒感染时发生改变,而通过 PAV-431 的治疗则可在很大程度上恢复。一种先进的类似物 PAV-104 被证明对病毒改变的靶点具有选择性,从而避免了对宿主的毒性。我们的研究结果为了解宿主-病毒界面并对其进行药物治疗提供了一种新的范式,从而为治疗呼吸道病毒性疾病提供了一种新的临床治疗策略。
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引用次数: 0
Oestrogen receptor positive breast cancer and its embedded mechanism: breast cancer resistance to conventional drugs and related therapies, a review. 雌激素受体阳性乳腺癌及其内在机制:乳腺癌对传统药物和相关疗法的耐药性综述。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-06-01 Epub Date: 2024-06-19 DOI: 10.1098/rsob.230272
Manu Yadav, Ishita Vaishkiar, Ananya Sharma, Akanksha Shukla, Aradhana Mohan, Madhuri Girdhar, Anil Kumar, Tabarak Malik, Anand Mohan

Traditional medication and alternative therapies have long been used to treat breast cancer. One of the main problems with current treatments is that there is an increase in drug resistance in the cancer cells owing to genetic differences such as mutational changes, epigenetic changes and miRNA (microRNA) alterations such as miR-1246, miR-298, miR-27b and miR-33a, along with epigenetic modifications, such as Histone3 acetylation and CCCTC-Binding Factor (CTCF) hypermethylation for drug resistance in breast cancer cell lines. Certain forms of conventional drug resistance have been linked to genetic changes in genes such as ABCB1, AKT, S100A8/A9, TAGLN2 and NPM. This review aims to explore the current approaches to counter breast cancer, the action mechanism, along with novel therapeutic methods endowing potential drug resistance. The investigation of novel therapeutic approaches sheds light on the phenomenon of drug resistance including genetic variations that impact distinct forms of oestrogen receptor (ER) cancer, genetic changes, epigenetics-reported resistance and their identification in patients. Long-term effective therapy for breast cancer includes selective oestrogen receptor modulators, selective oestrogen receptor degraders and genetic variations, such as mutations in nuclear genes, epigenetic modifications and miRNA alterations in target proteins. Novel research addressing combinational therapies including maytansine, photodynamic therapy, guajadiol, talazoparib, COX2 inhibitors and miRNA 1246 inhibitors have been developed to improve patient survival rates.

长期以来,传统药物和替代疗法一直被用于治疗乳腺癌。目前治疗方法的主要问题之一是,由于基因差异,如突变、表观遗传变化和 miRNA(microRNA)改变,如 miR-1246、miR-298、miR-27b 和 miR-33a,以及表观遗传修饰,如组蛋白 3 乙酰化和 CCCTC 结合因子(CTCF)超甲基化,导致乳腺癌细胞株耐药性增加。某些形式的常规耐药性与 ABCB1、AKT、S100A8/A9、TAGLN2 和 NPM 等基因的遗传变化有关。这篇综述旨在探讨目前对抗乳腺癌的方法、作用机制以及具有潜在耐药性的新型治疗方法。对新型治疗方法的研究揭示了耐药性现象,包括影响不同形式雌激素受体(ER)癌的基因变异、基因变化、表观遗传学报告的耐药性及其在患者中的识别。乳腺癌的长期有效疗法包括选择性雌激素受体调节剂、选择性雌激素受体降解剂和基因变异,如核基因突变、表观遗传修饰和靶蛋白中 miRNA 的改变。为提高患者的生存率,已开发出针对组合疗法的新型研究,包括美坦素、光动力疗法、瓜加地尔、talazoparib、COX2 抑制剂和 miRNA 1246 抑制剂。
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引用次数: 0
CNTN4 modulates neural elongation through interplay with APP. CNTN4 通过与 APP 的相互作用调节神经伸长。
IF 4.5 3区 生物学 Q1 BIOCHEMISTRY & MOLECULAR BIOLOGY Pub Date : 2024-05-01 Epub Date: 2024-05-15 DOI: 10.1098/rsob.240018
Rosemary A Bamford, Amila Zuko, Madeline Eve, Jan J Sprengers, Harm Post, Renske L R E Taggenbrock, Dominique Fäβler, Annika Mehr, Owen J R Jones, Aurimas Kudzinskas, Josan Gandawijaya, Ulrike C Müller, Martien J H Kas, J Peter H Burbach, Asami Oguro-Ando

The neuronal cell adhesion molecule contactin-4 (CNTN4) is genetically associated with autism spectrum disorder (ASD) and other psychiatric disorders. Cntn4-deficient mouse models have previously shown that CNTN4 plays important roles in axon guidance and synaptic plasticity in the hippocampus. However, the pathogenesis and functional role of CNTN4 in the cortex has not yet been investigated. Our study found a reduction in cortical thickness in the motor cortex of Cntn4 -/- mice, but cortical cell migration and differentiation were unaffected. Significant morphological changes were observed in neurons in the M1 region of the motor cortex, indicating that CNTN4 is also involved in the morphology and spine density of neurons in the motor cortex. Furthermore, mass spectrometry analysis identified an interaction partner for CNTN4, confirming an interaction between CNTN4 and amyloid-precursor protein (APP). Knockout human cells for CNTN4 and/or APP revealed a relationship between CNTN4 and APP. This study demonstrates that CNTN4 contributes to cortical development and that binding and interplay with APP controls neural elongation. This is an important finding for understanding the physiological function of APP, a key protein for Alzheimer's disease. The binding between CNTN4 and APP, which is involved in neurodevelopment, is essential for healthy nerve outgrowth.

神经细胞粘附分子接触素-4(CNTN4)与自闭症谱系障碍(ASD)和其他精神疾病有遗传关联。Cntn4缺陷小鼠模型曾表明,CNTN4在海马轴突导向和突触可塑性中发挥重要作用。然而,CNTN4 在大脑皮层中的发病机制和功能作用尚未得到研究。我们的研究发现,Cntn4 -/-小鼠运动皮层厚度减少,但皮层细胞迁移和分化不受影响。在运动皮层 M1 区的神经元中观察到了显著的形态变化,这表明 CNTN4 也参与了运动皮层神经元的形态和脊柱密度。此外,质谱分析确定了 CNTN4 的相互作用伙伴,证实了 CNTN4 与淀粉样前体蛋白(APP)之间的相互作用。敲除 CNTN4 和/或 APP 的人体细胞显示了 CNTN4 与 APP 之间的关系。这项研究表明,CNTN4有助于大脑皮层的发育,它与APP的结合和相互作用控制着神经的伸长。这是了解阿尔茨海默病关键蛋白 APP 生理功能的重要发现。CNTN4 与参与神经发育的 APP 之间的结合对于神经的健康生长至关重要。
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引用次数: 0
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