本文介绍了Phenomics期刊2024年第二期收录文章合集，文章概览如下，请查收！

（Phenomics期刊2024年第二期封面图）

01

A Proactive Intervention Study in Metabolic Syndrome High-Risk Populations Using Phenome-Based Actionable P4 Medicine Strategy

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DOI: 

https://doi.org/10.1007/s43657-023-00115-z

引用格式：

Huang, Q., Hu, Z., Zheng, Q. et al. A Proactive Intervention Study in Metabolic Syndrome High-Risk Populations Using Phenome-Based Actionable P4 Medicine Strategy. Phenomics 4, 91–108 (2024). https://doi.org/10.1007/s43657-023-00115-z

该研究揭露了遗传、表型、干预方式三者之间的相关性，提供了一个在日常生活中可操作的主动干预示例，也象征着人类在应用系统生物学方法来管理代谢综合征等复杂慢病迈出的重要一步。

Abstract

The integration of predictive, preventive, personalized, and participatory (P4) healthcare advocates proactive intervention, including dietary supplements and lifestyle interventions for chronic disease. Personal profiles include deep phenotypic data and genetic information, which are associated with chronic diseases, can guide proactive intervention. However, little is known about how to design an appropriate intervention mode to precisely intervene with personalized phenome-based data. Here, we report the results of a 3-month study on 350 individuals with metabolic syndrome high-risk that we named the Pioneer 350 Wellness project (P350). We examined: (1) longitudinal (two times) phenotypes covering blood lipids, blood glucose, homocysteine (HCY), and vitamin D3 (VD3), and (2) polymorphism of genes related to folic acid metabolism. Based on personalized data and questionnaires including demographics, diet and exercise habits information, coaches identified 'actionable possibilities', which combined exercise, diet, and dietary supplements. After a 3-month proactive intervention, two-thirds of the phenotypic markers were significantly improved in the P350 cohort. Specifically, we found that dietary supplements and lifestyle interventions have different effects on phenotypic improvement. For example, dietary supplements can result in a rapid recovery of abnormal HCY and VD3 levels, while lifestyle interventions are more suitable for those with high body mass index (BMI), but almost do not help the recovery of HCY. Furthermore, although people who implemented only one of the exercise or diet interventions also benefited, the effect was not as good as the combined exercise and diet interventions. In a subgroup of 226 people, we examined the association between the polymorphism of genes related to folic acid metabolism and the benefits of folate supplementation to restore a normal HCY level. We found people with folic acid metabolism deficiency genes are more likely to benefit from folate supplementation to restore a normal HCY level. Overall, these results suggest: (1) phenome-based data can guide the formulation of more precise and comprehensive interventions, and (2) genetic polymorphism impacts clinical responses to interventions. Notably, we provide a proactive intervention example that is operable in daily life, allowing people with different phenome-based data to design the appropriate intervention protocol including dietary supplements and lifestyle interventions.

02

Plasma-Free Blood as a Potential Alternative to Whole Blood for Transcriptomic Analysis

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DOI: 

https://doi.org/10.1007/s43657-023-00121-1

引用格式：

Chen, Q., Guo, X., Wang, H. et al. Plasma-Free Blood as a Potential Alternative to Whole Blood for Transcriptomic Analysis. Phenomics 4, 109–124 (2024). https://doi.org/10.1007/s43657-023-00121-1

该研究评估在转录组学分析中使用来自无血浆血（PFB）和无血清血液（SFB）的RNA样品替代全血（WB）的适用性。该文研究者对不同应用场景下的WB、PFB和SFB样品进行了比较分析。结果表明，PFB样品在蛋白质编码基因表达模式、差异表达基因检测和免疫学特征方面与WB样品具有更大的相似性，表明PFB可以作为WB的替代品进行转录组学分析。该研究有助于优化血液样本利用和推进精准医学研究。

Abstract

RNA sequencing (RNAseq) technology has become increasingly important in precision medicine and clinical diagnostics, and emerged as a powerful tool for identifying protein-coding genes, performing differential gene analysis, and inferring immune cell composition. Human peripheral blood samples are widely used for RNAseq, providing valuable insights into individual biomolecular information. Blood samples can be classified as whole blood (WB), plasma, serum, and remaining sediment samples, including plasma-free blood (PFB) and serum-free blood (SFB) samples that are generally considered less useful byproducts during the processes of plasma and serum separation, respectively. However, the feasibility of using PFB and SFB samples for transcriptome analysis remains unclear. In this study, we aimed to assess the suitability of employing PFB or SFB samples as an alternative RNA source in transcriptomic analysis. We performed a comparative analysis of WB, PFB, and SFB samples for different applications. Our results revealed that PFB samples exhibit greater similarity to WB samples than SFB samples in terms of protein-coding gene expression patterns, detection of differentially expressed genes, and immunological characterizations, suggesting that PFB can serve as a viable alternative to WB for transcriptomic analysis. Our study contributes to the optimization of blood sample utilization and the advancement of precision medicine research.

03

Bronchoalveolar Lavage Fluid Microbiota is Associated with the Diagnosis and Prognosis Evaluation of Lung Cancer

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DOI：

https://doi.org/10.1007/s43657-023-00135-9

引用格式：

Cheng, C., Wang, Z., Ding, C. et al. Bronchoalveolar Lavage Fluid Microbiota is Associated with the Diagnosis and Prognosis Evaluation of Lung Cancer. Phenomics 4, 125–137 (2024). https://doi.org/10.1007/s43657-023-00135-9

该研究揭示肺癌和肺良性疾病患者肺部菌群组成及多样性特征，比较非小细胞肺癌（NSCLC）和小细胞肺癌(SCLC)患者肺部菌群的差异，再联合临床病理、随访数据等临床信息进一步探索肺部菌群在肺癌诊断和预后评估方面的作用，为后续NSCLC或SCLC与某种微生物相互作用的机制研究提供支撑，为创建肺癌患者肺部菌群的认知策略提供丰富数据。

Abstract

The gut microbiota and cancer have been demonstrated to be closely related. However, few studies have explored the bronchoalveolar lavage fluid (BALF) microbiota in patients with lung cancer (LC), specifically the microbiota related to progression-free survival (PFS) in LC. A total of 216 BALF samples were collected including 166 LC and 50 benign pulmonary disease (N-LC) samples, and further sequenced using 16S rRNA amplicon sequencing. Enrolled LC patients were followed up, the therapeutic efficacy was assessed, and PFS was calculated. The associated clinical and microbiota sequencing data were deeply analysed. Distinct differences in the microbial profiles were evident in the lower airways of patients with LC and N-LC, which was also found between non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC). A combined random forest model was built to distinguish NSCLC from SCLC and reached area under curves (AUCs) of 0.919 (95% CI 86.69–97.1%) and 0.893 (95% CI 79.39–99.29%) in the training and test groups, respectively. The lower alpha diversity of the BALF microbiota in NSCLC patients was significantly associated with reduced PFS, although this link was not observed in SCLC. Specifically, NSCLC with a higher abundance of f_Lachnospiraceae, s_Prevotella nigrescens and f_[Mogibacteriaceae] achieved longer PFS. The enrichment of o_Streptophyta and g_Prevotella was observed in SCLC with worse PFS. This study provided a detailed description of the characteristics of BALF microbiota in patients with NSCLC and SCLC simultaneously and provided insights into the role of the diagnosis and prognosis evaluation.

04

Quantitative Assessment of Ultraviolet-Induced Erythema and Tanning Responses in the Han Chinese Population

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DOI：

https://doi.org/10.1007/s43657-023-00105-1

引用格式：

Ma, Y., Tan, Y., Hu, Y. et al. Quantitative Assessment of Ultraviolet-Induced Erythema and Tanning Responses in the Han Chinese Population. Phenomics 4, 138–145 (2024). https://doi.org/10.1007/s43657-023-00105-1

该研究说明在相对安全的紫外线剂量45 mJ/cm²下，紫外线照射后第1天的ΔE和第7天的ΔM分别是评估紫外线诱导的红斑反应和晒黑能力的理想指标，并建立了定量评估紫外线诱导的红斑反应和晒黑反应的标准方法。

Abstract

Ultraviolet radiation (UVR) can induce erythema and tanning responses with strong diversity within and between populations, but there were no precise method for evaluating the variation in these responses. In this study, we assessed the time course of ultraviolet (UV)-induced responses based on the erythema index (EI) and melanin index (MI) over 14 consecutive days in a pilot cohort study (N = 31). From safety evaluations, we found that no skin blisters occurred at a UV dosage of 45 mJ/cm2, but there were significant skin reactions. Regardless of UV dosage, the measurements and variances of EI peaked on day 1 after UV irradiation, and those of MI peaked on day 7. Dose–response curves, including erythema dose–response (EDR) and melanin dose–response (MDR), could measure UV-induced phenotypes sensitively but more laboriously. As an alternative, we directly represented the UV-induced erythema and tanning responses using the erythema increment (ΔE) and melanin increment (ΔM). We found that ΔE and ΔM at 45 mJ/cm2 significantly correlated with erythema dose–response (EDR) (R2 > 0.9) and melanin dose–response (MDR) (R2 > 0.9), respectively. Therefore, ΔE and ΔM on day 1 and day 7 after UV irradiation at a dosage of 45 mJ/cm2 might be ideal alternative measures for assessing individual erythema and tanning responses. Then, a second cohort (N = 664) was recruited to validate the UV-induced phenotypes, and, as expected, the results of the two cohorts were in agreement. Therefore, we developed a simplified and precise method to quantify the UV-induced erythema response and tanning ability for the Han Chinese population.

05

Clinical Application of Polygenic Risk Score in IgA Nephropathy

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DOI：

https://doi.org/10.1007/s43657-023-00138-6

引用格式：

Xu, L., Gan, T., Chen, P. et al. Clinical Application of Polygenic Risk Score in IgA Nephropathy. Phenomics 4, 146–157 (2024). https://doi.org/10.1007/s43657-023-00138-6

该研究表明，风险变异的负担越大，IgA肾病发病越早，不良预后的风险越高。由于基因变异“与生俱来”，将GRS纳入临床研究可以提供有价值的风险分层指导，以识别需要定期尿检的个体，以便于早期发现IgA肾病患者，并为其提供早期干预以延缓疾病进展。

Abstract

Genome-wide association studies (GWASs) have identified 30 independent genetic variants associated with IgA nephropathy (IgAN). A genetic risk score (GRS) represents the number of risk alleles carried and thus captures an individual's genetic risk. However, whether and which polygenic risk score crucial for the evaluation of any potential personal or clinical utility on risk and prognosis are still obscure. We constructed different GRS models based on different sets of variants, which were top single nucleotide polymorphisms (SNPs) reported in the previous GWASs. The case–control GRS analysis included 3365 IgAN patients and 8842 healthy individuals. The association between GRS and clinical variability, including age at diagnosis, clinical parameters, Oxford pathology classification, and kidney prognosis was further evaluated in a prospective cohort of 1747 patients. Three GRS models (15 SNPs, 21 SNPs, and 55 SNPs) were constructed after quality control. The patients with the top 20% GRS had 2.42—(15 SNPs, p = 8.12 × 10–40), 3.89—(21 SNPs, p = 3.40 × 10–80) and 3.73—(55 SNPs, p = 6.86 × 10–81) fold of risk to develop IgAN compared to the patients with the bottom 20% GRS, with area under the receiver operating characteristic curve (AUC) of 0.59, 0.63, and 0.63 in group discriminations, respectively. A positive correlation between GRS and microhematuria, mesangial hypercellularity, segmental glomerulosclerosis and a negative correlation on the age at diagnosis, body mass index (BMI), mean arterial pressure (MAP), serum C3, triglycerides can be observed. Patients with the top 20% GRS also showed a higher risk of worse prognosis for all three models (1.36, 1.42, and 1.36 fold of risk) compared to the remaining 80%, whereas 21 SNPs model seemed to show a slightly better fit in prediction. Collectively, a higher burden of risk variants is associated with earlier disease onset and a higher risk of a worse prognosis. This may be informational in translating knowledge on IgAN genetics into disease risk prediction and patient stratification.

06

Identification of Key Factors in Cartilage Tissue During the Progression of Osteoarthritis Using a Non-targeted Metabolomics Strategy

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DOI：

https://doi.org/10.1007/s43657-023-00112-2

引用格式：

Zhu, Z., Weng, S., Zheng, F. et al. Identification of Poly(ADP-ribose) Polymerase 9 (PARP9) as a Potent Suppressor for Mycobacterium tuberculosis Infection. Phenomics 4, 158–170 (2024). https://doi.org/10.1007/s43657-023-00112-2

该研究发现TB(Tuberculosis)患者和感染Mtb小鼠中多个PARPs的转录水平发生显著变化。分枝杆菌感染期间，PARP9、PARP10、PARP12和PARP14的 mRNA和蛋白水平显著升高。进一步研究发现宿主PARP9可抑制Ms的胞内感染和增殖能力，揭示了PARP9作为分枝杆菌感染的有效抑制因子的功能，为TB患者的防治提供了新的思路。

Abstract

ADP-ribosylation is a reversible and dynamic post-translational modification mediated by ADP-ribosyltransferases (ARTs). Poly(ADP-ribose) polymerases (PARPs) are an important family of human ARTs. ADP-ribosylation and PARPs have crucial functions in host-pathogen interaction, especially in viral infections. However, the functions and potential molecular mechanisms of ADP-ribosylation and PARPs in Mycobacterium infection remain unknown. In this study, bioinformatics analysis revealed significantly changed expression levels of several PARPs in tuberculosis patients compared to healthy individuals. Moreover, the expression levels of these PARPs returned to normal following tuberculosis treatment. Then, the changes in the expression levels of PARPs during Mycobacterium infection were validated in Tohoku Hospital Pediatrics-1 (THP1)-induced differentiated macrophages infected with Mycobacterium model strains bacillus Calmette-Guerin (BCG) and in human lung adenocarcinoma A549 cells infected with Mycobacterium smegmatis (Ms), respectively. The mRNA levels of PARP9, PARP10, PARP12, and PARP14 were most significantly increased during infection, with corresponding increases in protein levels, indicating the possible biological functions of these PARPs during Mycobacterium infection. In addition, the biological function of host PARP9 in Mycobacterium infection was further studied. PARP9 deficiency significantly increased the infection efficiency and intracellular proliferation ability of Ms, which was reversed by the reconstruction of PARP9. Collectively, this study updates the understanding of changes in PARP expression in Mycobacterium infection and provides evidence supporting PARP9 as a potent suppressor for Mycobacterium infection.

3D Models of Sarcomas: The Next-generation Tool for Personalized Medicine

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DOI：

https://doi.org/10.1007/s43657-023-00111-3

引用格式：

Xu, R., Chen, R., Tu, C. et al. 3D Models of Sarcomas: The Next-generation Tool for Personalized Medicine. Phenomics 4, 171–186 (2024). https://doi.org/10.1007/s43657-023-00111-3

该综述讨论了肉瘤类器官培养的最新进展，重点关注它们作为药物筛选和生物样本库工具的潜力。强调了肉瘤类器官用于研究基因调控、耐药性、转移和免疫相互作用机制的方式。肉瘤类器官已被证明在体外系统中保留了体内生物学的特征，使其成为肉瘤研究更具代表性的模型。该综述表明，肉瘤类器官为该领域的转化研究提供了一条潜在的前进道路，并可能为肉瘤患者开发个性化疗法提供平台。

Abstract

Sarcoma is a complex and heterogeneous cancer that has been difficult to study in vitro. While two-dimensional (2D) cell cultures and mouse models have been the dominant research tools, three-dimensional (3D) culture systems such as organoids have emerged as promising alternatives. In this review, we discuss recent developments in sarcoma organoid culture, with a focus on their potential as tools for drug screening and biobanking. We also highlight the ways in which sarcoma organoids have been used to investigate the mechanisms of gene regulation, drug resistance, metastasis, and immune interactions. Sarcoma organoids have shown to retain characteristics of in vivo biology within an in vitro system, making them a more representative model for sarcoma research. Our review suggests that sarcoma organoids offer a potential path forward for translational research in this field and may provide a platform for developing personalized therapies for sarcoma patients.

08

The Critical Role of the Shroom Family Proteins in Morphogenesis, Organogenesis and Disease

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DOI：

https://doi.org/10.1007/s43657-023-00119-9

引用格式：

Liu, W., Xiu, L., Zhou, M. et al. The Critical Role of the Shroom Family Proteins in Morphogenesis, Organogenesis and Disease. Phenomics 4, 187–202 (2024). https://doi.org/10.1007/s43657-023-00119-9

Shroom (Shrm)家族的肌动蛋白结合蛋白具有一个独特且高度保守的Apx/Shrm结构域2 (ASD2)基元。Shroom蛋白指导rho相关激酶(ROCK)的亚细胞定位，ROCK通过磷酸化和激活非肌肉肌球蛋白II的能力重塑肌动球蛋白细胞骨架并改变细胞形态。因此，Shrm-ROCK复合物对细胞形状和许多组织的发育至关重要，包括神经管、眼睛、肠、心脏和血管系统。重要的是，Shrm蛋白的结构和表达也与神经管缺陷、慢性肾脏疾病、癌症转移和X连锁智力低下有关。因此，更好地了解Shrm介导的信号转导途径对于开发新的治疗策略以减少由异常Shrm蛋白引起的损伤至关重要。该文提供了各种Shrm蛋白及其在形态发生和疾病中的作用的全面概述。

Abstract

The Shroom (Shrm) family of actin-binding proteins have a unique and highly conserved Apx/Shrm Domain 2 (ASD2) motif. Shroom protein directs the subcellular localization of Rho-associated kinase (ROCK), which remodels the actomyosin cytoskeleton and changes cellular morphology via its ability to phosphorylate and activate non-muscle myosin II. Therefore, the Shrm-ROCK complex is critical for the cellular shape and the development of many tissues, including the neural tube, eye, intestines, heart, and vasculature system. Importantly, the structure and expression of Shrm proteins are also associated with neural tube defects, chronic kidney disease, metastasis of carcinoma, and X-link mental retardation. Therefore, a better understanding of Shrm-mediated signaling transduction pathways is essential for the development of new therapeutic strategies to minimize damage resulting in abnormal Shrm proteins. This paper provides a comprehensive overview of the various Shrm proteins and their roles in morphogenesis and disease.

09

Measurement of Energy Expenditure by Indirect Calorimetry with a Whole-Room Calorimeter

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DOI：

https://doi.org/10.1007/s43657-023-00127-9

引用格式：

Zhou, G., Bao, K., Xiao, H. et al. Measurement of Energy Expenditure by Indirect Calorimetry with a Whole-Room Calorimeter. Phenomics 4, 203–212 (2024). https://doi.org/10.1007/s43657-023-00127-9

该研究表明，随着在临床和实验研究中评估代谢状态的重要性不断增长，对于代谢状态的研究不断深入，能量代谢测量设备的应用有望为观察生理病理状态提供更加全面的视角，进而为探索相关机制提供潜在支持。

Abstract

Energy plays a vital role in biological processes. To assess energy metabolism status in a large population cohort, the standard operating procedure for measuring energy expenditure measurement using a whole-room calorimeter was purposed in this study. This protocol illustrates the procedure and specific details for validating methanol burning and evaluating the metabolic status of volunteers. In metabolic status evaluation, the 1) O2 consumption, 2) CO2 production, 3) energy expenditure, and 4) respiratory exchange ratio were first measured at resting and provided as basic phenotype items in Human Phenotype Atlas. Besides, it includes the procedure and results for measuring exercise-related activity thermogenesis and evaluating the impact of environmental temperature on energy metabolism. These results demonstrate the broader utility of the whole-room calorimeter. The implementation of this protocol is expected to enhance the data comparability in Human Phenotype Atla and provide a valuable reference for metabolism-related studies.

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