Single-nucleus transcriptomics uncovers a geroprotective role of YAP in primate gingival aging.

Aging has a profound impact on the gingiva and significantly increases its susceptibility to periodontitis, a worldwide prevalent inflammatory disease. However, a systematic characterization and comprehensive understanding of the regulatory mechanism underlying gingival aging is still lacking. Here, we systematically dissected the phenotypic characteristics of gingiva during aging in primates and constructed the first single-nucleus transcriptomic landscape of gingival aging, by which a panel of cell type-specific signatures were elucidated. Epithelial cells were identified as the most affected cell types by aging in the gingiva. Further analyses pinpointed the crucial role of YAP in epithelial self-renew and homeostasis, which declined during aging in epithelial cells, especially in basal cells. The decline of YAP activity during aging was confirmed in the human gingival tissues, and downregulation of YAP in human primary gingival keratinocytes recapitulated the major phenotypic defects observed in the aged primate gingiva while overexpression of YAP showed rejuvenation effects. Our work provides an in-depth understanding of gingival aging and serves as a rich resource for developing novel strategies to combat aging-associated gingival diseases, with the ultimate goal of advancing periodontal health and promoting healthy aging.

Aging induces region-specific dysregulation of hormone synthesis in the primate adrenal gland.

Adrenal glands, vital for steroid secretion and the regulation of metabolism, stress responses and immune activation, experience age-related decline, impacting systemic health. However, the regulatory mechanisms underlying adrenal aging remain largely uninvestigated. Here we established a single-nucleus transcriptomic atlas of both young and aged primate suprarenal glands, identifying lipid metabolism and steroidogenic pathways as core processes impacted by aging. We found dysregulation in centripetal adrenocortical differentiation in aged adrenal tissues and cells in the zona reticularis region, responsible for producing dehydroepiandrosterone sulfate (DHEA-S), were highly susceptible to aging, reflected by senescence, exhaustion and disturbed hormone production. Remarkably, LDLR was downregulated in all cell types of the outer cortex, and its targeted inactivation in human adrenal cells compromised cholesterol uptake and secretion of dehydroepiandrosterone sulfate, as observed in aged primate adrenal glands. Our study provides crucial insights into endocrine physiology, holding therapeutic promise for addressing aging-related adrenal insufficiency and delaying systemic aging.

Decoding aging-dependent regenerative decline across tissues at single-cell resolution.

Regeneration across tissues and organs exhibits significant variation throughout the body and undergoes a progressive decline with age. To decode the relationships between aging and regenerative capacity, we conducted a comprehensive single-cell transcriptome analysis of regeneration in eight tissues from young and aged mice. We employed diverse analytical models to study tissue regeneration and unveiled the intricate cellular and molecular mechanisms underlying the attenuated regenerative processes observed in aged tissues. Specifically, we identified compromised stem cell mobility and inadequate angiogenesis as prominent contributors to this age-associated decline in regenerative capacity. Moreover, we discovered a unique subset of Arg1+ macrophages that were activated in young tissues but suppressed in aged regenerating tissues, suggesting their important role in age-related immune response disparities during regeneration. This study provides a comprehensive single-cell resource for identifying potential targets for interventions aimed at enhancing regenerative outcomes in the aging population.

Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration.

Hair loss affects millions of people at some time in their life, and safe and efficient treatments for hair loss are a significant unmet medical need. We report that topical delivery of quercetin (Que) stimulates resting hair follicles to grow with rapid follicular keratinocyte proliferation and replenishes perifollicular microvasculature in mice. We construct dynamic single-cell transcriptome landscape over the course of hair regrowth and find that Que treatment stimulates the differentiation trajectory in the hair follicles and induces an angiogenic signature in dermal endothelial cells by activating HIF-1α in endothelial cells. Skin administration of a HIF-1α agonist partially recapitulates the pro-angiogenesis and hair-growing effects of Que. Together, these findings provide a molecular understanding for the efficacy of Que in hair regrowth, which underscores the translational potential of targeting the hair follicle niche as a strategy for regenerative medicine, and suggest a route of pharmacological intervention that may promote hair regrowth.

Single-nucleus transcriptomics reveals a gatekeeper role for FOXP1 in primate cardiac aging.

Aging poses a major risk factor for cardiovascular diseases, the leading cause of death in the aged population. However, the cell type-specific changes underlying cardiac aging are far from being clear. Here, we performed single-nucleus RNA-sequencing analysis of left ventricles from young and aged cynomolgus monkeys to define cell composition changes and transcriptomic alterations across different cell types associated with age. We found that aged cardiomyocytes underwent a dramatic loss in cell numbers and profound fluctuations in transcriptional profiles. Via transcription regulatory network analysis, we identified FOXP1, a core transcription factor in organ development, as a key downregulated factor in aged cardiomyocytes, concomitant with the dysregulation of FOXP1 target genes associated with heart function and cardiac diseases. Consistently, the deficiency of FOXP1 led to hypertrophic and senescent phenotypes in human embryonic stem cell-derived cardiomyocytes. Altogether, our findings depict the cellular and molecular landscape of ventricular aging at the single-cell resolution, and identify drivers for primate cardiac aging and potential targets for intervention against cardiac aging and associated diseases.

Single-cell transcriptomic atlas of mouse cochlear aging.

Progressive functional deterioration in the cochlea is associated with age-related hearing loss (ARHL). However, the cellular and molecular basis underlying cochlear aging remains largely unknown. Here, we established a dynamic single-cell transcriptomic landscape of mouse cochlear aging, in which we characterized aging-associated transcriptomic changes in 27 different cochlear cell types across five different time points. Overall, our analysis pinpoints loss of proteostasis and elevated apoptosis as the hallmark features of cochlear aging, highlights unexpected age-related transcriptional fluctuations in intermediate cells localized in the stria vascularis (SV) and demonstrates that upregulation of endoplasmic reticulum (ER) chaperon protein HSP90AA1 mitigates ER stress-induced damages associated with aging. Our work suggests that targeting unfolded protein response pathways may help alleviate aging-related SV atrophy and hence delay the progression of ARHL.

A Single-Cell Transcriptomic Atlas of Human Skin Aging.

Skin undergoes constant self-renewal, and its functional decline is a visible consequence of aging. Understanding human skin aging requires in-depth knowledge of the molecular and functional properties of various skin cell types. We performed single-cell RNA sequencing of human eyelid skin from healthy individuals across different ages and identified eleven canonical cell types, as well as six subpopulations of basal cells. Further analysis revealed progressive accumulation of photoaging-related changes and increased chronic inflammation with age. Transcriptional factors involved in the developmental process underwent early-onset decline during aging. Furthermore, inhibition of key transcription factors HES1 in fibroblasts and KLF6 in keratinocytes not only compromised cell proliferation, but also increased inflammation and cellular senescence during aging. Lastly, we found that genetic activation of HES1 or pharmacological treatment with quercetin alleviated cellular senescence of dermal fibroblasts. These findings provide a single-cell molecular framework of human skin aging, providing a rich resource for developing therapeutic strategies against aging-related skin disorders.

Achieving Efficient and Privacy-Preserving k-NN Query for Outsourced eHealthcare Data.

The boom of Internet of Things devices promotes huge volumes of eHealthcare data will be collected and aggregated at eHealthcare provider. With the help of these health data, eHealthcare provider can offer reliable data service (e.g., k-NN query) to doctors for better diagnosis. However, the IT facility in the eHealthcare provider is incompetent with the huge volumes of eHealthcare data, so one popular solution is to deploy a powerful cloud and appoint the cloud to execute the k-NN query service. In this case, since the eHealthcare data are very sensitive yet cloud servers are not fully trusted, directly executing the k-NN query service in the cloud inevitably incurs privacy challenges. Apart from the privacy issues, efficiency issues also need to be taken into consideration because achieving privacy requirement will incur additional computational cost. However, existing focuses on k-NN query do not (fully) consider the data privacy or are inefficient. For instance, the best computational complexity of k-NN query over encrypted eHealthcare data in the cloud is as large as [Formula: see text], where N is the total number of data. In this paper, aiming at addressing the privacy and efficiency challenges, we design an efficient and privacy-preserving k-NN query scheme for encrypted outsourced eHealthcare data. Our proposed scheme is characterized by integrating the k d-tree with the homomorphic encryption technique for efficient storing encrypted data in the cloud and processing privacy-preserving k-NN query over encrypted data. Compared with existing works, our proposed scheme is more efficient in terms of privacy-preserving k-NN query. Specifically, our proposed scheme can achieve k-NN computation over encrypted data with [Formula: see text] computational complexity, where l and N respectively denote the data dimension and the total number of data. In addition, detailed security analysis shows that our proposed scheme is really privacy-preserving under our security model and performance evaluation also indicates that our proposed scheme is indeed efficient in terms of computational cost.

Exponential Arithmetic Based Self-Healing Group Key Distribution Scheme with Backward Secrecy under the Resource-Constrained Wireless Networks.

In resource-constrained wireless networks, resources such as storage space and communication bandwidth are limited. To guarantee secure communication in resource-constrained wireless networks, group keys should be distributed to users. The self-healing group key distribution (SGKD) scheme is a promising cryptographic tool, which can be used to distribute and update the group key for the secure group communication over unreliable wireless networks. Among all known SGKD schemes, exponential arithmetic based SGKD (E-SGKD) schemes reduce the storage overhead to constant, thus is suitable for the the resource-constrained wireless networks. In this paper, we provide a new mechanism to achieve E-SGKD schemes with backward secrecy. We first propose a basic E-SGKD scheme based on a known polynomial-based SGKD, where it has optimal storage overhead while having no backward secrecy. To obtain the backward secrecy and reduce the communication overhead, we introduce a novel approach for message broadcasting and self-healing. Compared with other E-SGKD schemes, our new E-SGKD scheme has the optimal storage overhead, high communication efficiency and satisfactory security. The simulation results in Zigbee-based networks show that the proposed scheme is suitable for the resource-restrained wireless networks. Finally, we show the application of our proposed scheme.

A Note on an Improved Self-Healing Group Key Distribution Scheme.

In 2014, Chen et al. proposed a one-way hash self-healing group key distribution scheme for resource-constrained wireless networks in the journal of Sensors (14(14):24358-24380, doi: 10.3390/ s141224358). They asserted that their Scheme 2 achieves mt-revocation capability, mt-wise forward secrecy, any-wise backward secrecy and has mt-wise collusion attack resistance capability. Unfortunately, this paper pointed out that their scheme does not satisfy the forward security, mt-revocation capability and mt-wise collusion attack resistance capability.

Stiffness of various pin configurations for pediatric supracondylar humeral fracture: a systematic review on biomechanical studies.

To compare the biomechanical stability of various pin configurations for pediatric supracondylar humeral fractures under varus, internal rotation, and extension conditions. After electronic retrieval, 11 biomechanical studies were included. Stiffness values of pin configurations under different loading conditions were extracted and pooled. There were no statistically significant differences between two cross pins and two divergent lateral pins on the basis of the 'Hamdi method' (P=0.249-0.737). An additional pin did not strengthen two-pin construct (P=0.124-0.367), but better stabilized fractures with medial comminution (P<0.01). Isolated lateral pins are preferable because of a better balance of a lower risk of nerve injury and comparable fixation strength. Limitations such as differences in experimental setup among recruited studies and small sample size may compromise the methodologic power of this study.