The ARPKD Protein DZIP1L Regulates Ciliary Protein Entry by Modulating the Architecture and Function of Ciliary Transition Fibers.

Serving as the cell's sensory antennae, primary cilia are linked to numerous human genetic diseases when they malfunction. DZIP1L, identified as one of the genetic causes of human autosomal recessive polycystic kidney disease (ARPKD), is an evolutionarily conserved ciliary basal body protein. Although it has been reported that DZIP1L is involved in the ciliary entry of PKD proteins, the underlying mechanism remains elusive. Here, an uncharacterized role of DZIP1L is reported in modulating the architecture and function of transition fibers (TFs), striking ciliary base structures essential for selective cilia gating. Using C. elegans as a model, C01G5.7 (hereafter termed DZIP-1) is identified as the sole homolog of DZIP1L, which specifically localizes to TFs. While DZIP-1 or ANKR-26 (the ortholog of ANKRD26) deficiency shows subtle impact on TFs, co-depletion of DZIP-1 and ANKR-26 disrupts TF assembly and cilia gating for soluble and membrane proteins, including the ortholog of ADPKD protein polycystin-2. Notably, the synergistic role for DZIP1L and ANKRD26 in the formation and function of TFs is highly conserved in mammalian cilia. Hence, the findings illuminate an evolutionarily conserved role of DZIP1L in TFs architecture and function, highlighting TFs as a vital part of the ciliary gate implicated in ciliopathies ARPKD.

PHF6-mediated transcriptional control of NSC via Ephrin receptors is impaired in the intellectual disability syndrome BFLS.

The plant homeodomain zinc-finger protein, PHF6, is a transcriptional regulator, and PHF6 germline mutations cause the X-linked intellectual disability (XLID) Börjeson-Forssman-Lehmann syndrome (BFLS). The mechanisms by which PHF6 regulates transcription and how its mutations cause BFLS remain poorly characterized. Here, we show genome-wide binding of PHF6 in the developing cortex in the vicinity of genes involved in central nervous system development and neurogenesis. Characterization of BFLS mice harbouring PHF6 patient mutations reveals an increase in embryonic neural stem cell (eNSC) self-renewal and a reduction of neural progenitors. We identify a panel of Ephrin receptors (EphRs) as direct transcriptional targets of PHF6. Mechanistically, we show that PHF6 regulation of EphR is impaired in BFLS mice and in conditional Phf6 knock-out mice. Knockdown of EphR-A phenocopies the PHF6 loss-of-function defects in altering eNSCs, and its forced expression rescues defects of BFLS mice-derived eNSCs. Our data indicate that PHF6 directly promotes Ephrin receptor expression to control eNSC behaviour in the developing brain, and that this pathway is impaired in BFLS.

Cyclic loading changes the taproot's tensile properties and reinforces the soil via the shrub's taproot in semi-arid areas, China.

This study aimed to reveal the soil reinforcement by shrub root systems after repeated stress from external forces, such as high winds and runoff, for extended periods in the wind-hydraulic compound erosion zone. Using the widely distributed Shandong mine area soil and water-conserving plant species, Caragana microphylla, Hippophae rhamnoides, and Artemisia ordosica, cyclic loading tests were conducted on taproots of the three plant species (1-5 mm diameter) via a TY8000 servo-type machine to investigate the taproots' tensile properties response to repeated loading-unloading using simulated high wind pulling and runoff scouring. Our study revealed that the tensile force was positively correlated with the root diameter but the tensile strength was negatively correlated under monotonic and cyclic loading of the three plants' taproots. However, after cyclic loading, the three plant species' taproots significantly enhanced the tensile force and strength more than monotonic loading (P < 0.05). The taproot force-displacement hysteresis curves of the three plant species revealed obvious cyclic characteristics. Structural equation modeling analysis revealed that root diameter and damage method directly affected the taproots' survival rate, reflecting their sustainable soil reinforcement capacity. The damage method significantly influenced the soil reinforcement more than the root diameter. Our findings reveal that the plant species' taproots can adapt more to the external environment and enhance their resistance to erosion after natural low perimeter erosion damage, effectively inducing soil reinforcement. Particularly, the taproots of Caragana microphylla have superior soil-fixing ability and can be used for ecological restoration.

Improved Antitumor Efficacy of a Dextran-based Docetaxel-coupled Conjugate against Triple-Negative Breast Cancer.

BACKGROUND: Most chemotherapeutic agents are characterized by poor water solubility and non-specific distribution. Polymer-based conjugates are promising strategies for overcoming these limitations. OBJECTIVE: This study aims to fabricate a polysaccharide, dextran-based, dual-drug conjugate by covalently grafting docetaxel (DTX) and docosahexaenoic acid (DHA) onto the bifunctionalized dextran through a long linker, and to investigate the antitumor efficacy of this conjugate against breast cancer. METHODS: DTX was firstly coupled with DHA and covalently bounded with the bifunctionalized dextran (100 kDa) through a long linker to produce a conjugate dextran-DHA-DTX (termed C-DDD). Cytotoxicity and cellular uptake of this conjugate were measured in vitro. Drug biodistribution and pharmacokinetics were investigated through liquid chromatography/mass spectrometry analysis. The inhibitory effects on tumor growth were evaluated in MCF-7- and 4T1-tumor-bearing mice. RESULTS: The loading capacity of the C-DDD for DTX was 15.90 (weight/weight). The C-DDD possessed good water solubility and was able to self-assemble into nanoparticles measuring 76.8 ± 5.5 nm. The maximum plasma concentration and area under the curve (0-∞) for the released DTX and total DTX from the C-DDD were significantly enhanced compared with the conventional DTX formulation. The C-DDD selectively accumulated in the tumor, with limited distribution was observed in normal tissues. The C-DDD exhibited greater antitumor activity than the conventional DTX in the triplenegative breast cancer model. Furthermore, the C-DDD nearly eliminated all MCF-7 tumors in nude mice without leading to systemic adverse effects. CONCLUSION: This dual-drug C-DDD has the potential to become a candidate for clinical application through the optimization of the linker.

Influence of unsaturated fatty acids on the antitumor activity of polymeric conjugates grafted with cabazitaxel against prostate cancer.

Cabazitaxel (CTX) is a medication used for treating metastatic prostate cancer. However, its effectiveness is majorly limited by its poor water solubility and lack of tumor targeting. In this study, three unsaturated fatty acids, GLA, ALA and DHA, were separately connected with CTX and then covalently attached to bifunctionalized dextran through a linker to produce three dual drug conjugates named dextran-GLA-CTX, dextran-ALA-CTX and dextran-DHA-CTX. The three conjugates displayed enhanced solubility of CTX in water and improved antitumor effects compared to the conventional CTX formulation. The results also confirmed that dextran-GLA-CTX exhibited the strongest antitumor activity, while dextran-DHA-CTX displayed less efficacy, as evaluated through xenografted nude mice bearing PC-3 and DU145 prostate cancer cells. Additionally, dextran-GLA-CTX showed greater inhibition of tumor growth than dextran-CTX. Moreover, the dextran-GLA-CTX conjugate was found to prolong the half-life of CTX in plasma and selectively accumulate in tumors. This study revealed that unsaturated fatty acids can enhance the antitumor activity of dextran-based conjugates grafted with CTX.

DNAJB4 suppresses breast cancer progression and promotes tumor immunity by regulating the Hippo signaling pathway.

PURPOSE: Breast cancer is the most common cancer worldwide. Low DNAJB4 expression levels are strongly correlated with poor prognosis in breast cancer patients. However, the molecular mechanism by which DNAJB4 regulates breast cancer progression is unclear. METHODS: The expression of DNAJB4 was validated in human breast cancer tissues, normal human breast tissues, and breast cancer cell lines. CCK-8, colony-forming, and wound healing assays were used to assess the biological effect of DNAJB4 overexpression on cell proliferation and migration in MCF-7 cell lines. Bioinformatic analysis was used to identify the DNAJB4 related pathways in breast cancer. Epithelial-mesenchymal transition (EMT)-related biomarkers and Hippo pathway components were quantified by Western blots. Luciferase and Western blot assays were used to validate which miRNA regulates DNAJB4. In addition, the effects of DNAJB4 on in vivo tumor growth were assessed in xenograft models. RESULTS: DNAJB4 was expressed at low levels in human breast cancer tissues and breast cancer cell lines and correlated with poor prognosis. DNAJB4 overexpression significantly inhibited cell proliferation and migration in vitro by activating the Hippo pathway. The dual-luciferase assay showed that hsa-miR-183-5p targeted DNAJB4. Moreover, the effects of DNAJB4 could be reversed by miR-183-5p. In addition, the expression of DNAJB4 was strongly correlated with immune infiltration levels. Notably, DNAJB4 overexpression markedly enhanced CD4 + and CD8 + T cells and reduced PD-L1 levels in 4T1 tumors via the Hippo pathway, which retarded tumor growth in a subcutaneous xenograft tumor mouse model of 4T1 cells. CONCLUSIONS: The present study demonstrated that DNAJB4 overexpression inhibited the malignant biological behavior of breast cancer by regulating the Hippo pathway and tumor immunosuppressive environment.

From Primary Cilia and Planar Cell Polarity to Kidney Injury and Repair.

Almost every cell in the kidney, including renal tubular epithelial cells, has a primary cilium, which is a membrane-bound, hair-like structure protruding from the cellular surface. Dysfunction of primary cilia has been linked to a wide spectrum of human genetic diseases, termed ciliopathies. Planar cell polarity (PCP) refers to the coordinated alignment of cells along the cell sheet or tissue plane, a fundamental process in embryo development and organogenesis. Interestingly, there is evidence that primary cilium and PCP are interconnected. However, very limited is known about the involvement of cilia and PCP in kidney injury and repair. By using cell and mouse models, we have demonstrated a protective role of primary cilia in acute kidney injury. Mechanistically, we unveiled a reciprocal promoting relationship between cilia and autophagy in kidney tubular cells, and, accordingly, cilia may protect tubular cells by enhancing autophagy. Our recent studies further demonstrated that PCP dysfunction exaggerates acute kidney injury and may also contribute to maladaptive kidney repair after acute kidney injury. These findings provide a novel dimension to further understanding kidney injury and repair from the standpoint of cell biology.

A stress-induced cilium-to-PML-NB route drives senescence initiation.

Cellular senescence contributes to tissue homeostasis and age-related pathologies. However, how senescence is initiated in stressed cells remains vague. Here, we discover that exposure to irradiation, oxidative or inflammatory stressors induces transient biogenesis of primary cilia, which are then used by stressed cells to communicate with the promyelocytic leukemia nuclear bodies (PML-NBs) to initiate senescence responses in human cells. Mechanistically, a ciliary ARL13B-ARL3 GTPase cascade negatively regulates the association of transition fiber protein FBF1 and SUMO-conjugating enzyme UBC9. Irreparable stresses downregulate the ciliary ARLs and release UBC9 to SUMOylate FBF1 at the ciliary base. SUMOylated FBF1 then translocates to PML-NBs to promote PML-NB biogenesis and PML-NB-dependent senescence initiation. Remarkably, Fbf1 ablation effectively subdues global senescence burden and prevents associated health decline in irradiation-treated mice. Collectively, our findings assign the primary cilium a key role in senescence induction in mammalian cells and, also, a promising target in future senotherapy strategies.

Identification of essential genes and immune cell infiltration in rheumatoid arthritis by bioinformatics analysis.

Rheumatoid arthritis (RA) is a common autoimmune disease that can lead to severe joint damage and disability. And early diagnosis and treatment of RA can avert or substantially slow the progression of joint damage in up to 90% of patients, thereby preventing irreversible disability. Previous research indicated that 50% of the risk for the development of RA is attributable to genetic factors, but the pathogenesis is not well understood. Thus, it is urgent to identify biomarkers to arrest RA before joints are irreversibly damaged. Here, we first use the Robust Rank Aggregation method (RRA) to identify the differentially expressed genes (DEGs) between RA and normal samples by integrating four public RA patients' mRNA expression data. Subsequently, these DEGs were used as the input for the weighted gene co-expression network analysis (WGCNA) approach to identify RA-related modules. The function enrichment analysis suggested that the RA-related modules were significantly enriched in immune-related actions. Then the hub genes were defined as the candidate genes. Our analysis showed that the expression levels of candidate genes were significantly associated with the RA immune microenvironment. And the results indicated that the expression of the candidate genes can use as predictors for RA. We hope that our method can provide a more convenient approach for the early diagnosis of RA.

Pesticide exposure and forage shortage in rice cropping system prevents honey bee colony establishment.

As one of the key stable crops to feed half of the world's population, how rice cropping system affects honey bee health regarding pesticide exposure and forage availability is under investigated. We predicted honey bees were stressed by high pesticide exposure and forage dearth in monoculture rice systems. Providing access to natural habitats is a typical approach to mitigate the negative impact of intensive agriculture on honey bees. We aimed to determine if bee colonies located in landscapes with more cover of forest habitat would collect more forage and be exposed to less pesticides. We selected beekeeping locations in rice dominated landscapes (as control), mosaic landscapes of rice and medium woodland (MW) cover, and landscapes of high woodland (HW) cover, respectively, in July when rice starts bloom and pesticides are commonly used. Colonies were inspected at a biweekly frequency from July to October with population growth and forage (nectar and pollen) availability estimated. Pollen and bees were collected in middle August for pesticide exposure analysis. We did not observe enhancement in forage availability and reduction in pesticide exposure in landscapes with increased forest habitat (i.e., MW or HW cover), and all colonies failed in the end. Other natural habitats that can supplement flower shortage periods in forest can be considered for supporting bee health. Our results suggest that forest should be carefully assessed for being incorporated into beekeeping management or pollinator conservation when forest phenology can be a factor to affect its impact as a natural habitat.

Polysaccharide dextran-based conjugate for selective co-delivery of two synergistic drugs docetaxel and docosahexaenoic acid to tumor cells.

Most chemotherapeutic agents are nonspecific distribution and cause systemic toxicities. Polysaccharide-based conjugates are promising strategies to overcome these drawbacks. To this end, two synergistic drugs docetaxel (DTX) and docosahexaenoic acid (DHA) were independently covalently bonded through individual linkers to dextran (100 kDa) to produce a novel dual-drug conjugate dextran-DHA-DTX. The single-drug conjugates dextran-DHA and dextran-DTX were also prepared for comparison. Fluorescent dye Cy7.5-based conjugates dextran-Cy7.5 and dextran-DHA-Cy7.5 were synthesized for cellular uptake study. The dual-drug conjugate dextran-DHA-DTX self-assembled into nanoparticles with the diameter of 102.3 ± 8.3 nm and demonstrated enhanced water solubility and improved pharmacokinetic profiles. Cellular uptake results showed that the dual-drug conjugate entered cells more than the parent DTX by determining the intracellular DTX contents via HPLC/MS analysis and by determining the fluorescent intensity of dextran-Cy7.5 and dextran-DHA-Cy7.5. Importantly, the dual-drug conjugate dextran-DHA-DTX significantly accumulated in tumor tissues and dramatically reduced the DTX concentrations in normal tissues. The dual-drug conjugate completely eradicated all the MCF-7 xenograft tumors without obvious side effects and showed more superior antitumor activity than parent DTX and single-drug conjugate dextran-DTX and dextran-DHA. Both in vitro and in vivo studies showed that DHA enhanced the antitumor activity of dextran-DTX. The polysaccharide dextran-based dual-drug conjugates may represent an effective way to improve the chemotherapeutic agents.

The Role of Primary Cilia-Associated Phosphoinositide Signaling in Development.

Primary cilia are microtube-based organelles that extend from the cell surface and function as biochemical and mechanical extracellular signal sensors. Primary cilia coordinate a series of signaling pathways during development. Cilia dysfunction leads to a pleiotropic group of developmental disorders, termed ciliopathy. Phosphoinositides (PIs), a group of signaling phospholipids, play a crucial role in development and tissue homeostasis by regulating membrane trafficking, cytoskeleton reorganization, and organelle identity. Accumulating evidence implicates the involvement of PI species in ciliary defects and ciliopathies. The abundance and localization of PIs in the cell are tightly regulated by the opposing actions of kinases and phosphatases, some of which are recently discovered in the context of primary cilia. Here, we review several cilium-associated PI kinases and phosphatases, including their localization along cilia, function in regulating the ciliary biology under normal conditions, as well as the connection of their disease-associated mutations with ciliopathies.

A Novel Dextran-Based Dual Drug Conjugate Targeted Tumors with High Biodistribution Ratio of Tumors to Normal Tissues.

Purpose: Most chemotherapeutic agents possess poor water solubility and show more significant accumulations in normal tissues than in tumor tissues, resulting in serious side effects. To this end, a novel dextran-based dual drug delivery system with high biodistribution ratio of tumors to normal tissues was developed. Methods: A bi-functionalized dextran was developed, and several negatively charged dextran-based dual conjugates containing two different types of drugs, docetaxel and docosahexaenoic acid (DTX and DHA, respectively) were synthesized. The structures of these conjugates were characterized using nuclear magnetic resonance and liquid chromatography/mass spectrometry (1H-NMR and LC/MS, respectively) analysis. Cell growth inhibition, apoptosis, cell cycle distribution, and cellular uptake were measured in vitro. Drug biodistribution and pharmacokinetics were investigated in mice bearing 4T1 tumors using LC/MS analysis. Drug biodistribution was also explored by in vivo imaging. The effects of these conjugates on tumor growth were evaluated in three mice models. Results: The dextran-docosahexaenoic acid (DHA)- docetaxel (DTX) conjugates caused a significant enhancement of DTX water solubility and improvement in pharmacokinetic characteristics. The optimized dextran-DHA-DTX conjugate A treatment produced a 2.1- to 15.5-fold increase in intra-tumoral DTX amounts for up to 96 h compared to parent DTX treatment. Meanwhile, the concentrations of DTX released from conjugate A in normal tissues were much lower than those of the parent DTX. This study demonstrated that DHA could lead to an improvement in the efficacy of the conjugates and that the conjugate with the shortest linker displayed more activity than conjugates with longer linkers. Moreover, conjugate A completely eradicated all MCF-7 xenograft tumors without causing any obvious side effects and totally outperformed both the conventional DTX formulation and Abraxane in mice. Conclusion: These dextran-based dual drug conjugates may represent an innovative tumor targeting drug delivery system that can selectively deliver anticancer agents to tumors.

Abnormal cerebellar network and effective connectivity in sudden and long-term sensorineural hearing loss.

Sudden sensorineural hearing loss (SSNHL) is a common otology emergency and some SSNHL will develop into a long-term hearing loss (LSNHL). However, whether SSNHL and LSNHL have similar psychiatric patterns remains unknown, as well as the neural substrates. Increasing evidence has proved that the cerebellar network plays a vital role in hearing, cognition processing, and emotion control. Thus, we recruited 20 right SSNHL (RSSNHL), 20 right LSNHL (RLSNHL), and 24 well-matched healthy controls to explore the cerebellar patterns among the three groups. Every participant underwent pure tone audiometry tests, neuropsychological evaluations, and MRI scanning. Independent component analysis (ICA) was carried out on the MRI data and the cerebellar network was extracted. Granger causality analysis (GCA) was conducted using the significant cerebellar region as a seed. Pearson's correlation analysis was computed between imaging characteristics and clinical features. ICA found the effect of group on right cerebellum lobule V for the cerebellar network. Then, we found decreased outflow from right cerebellum lobule V to right middle orbitofrontal cortex, inferior frontal gyrus, anterior cingulate cortex, superior temporal gyrus, and dorsal lateral prefrontal cortex in RSSNHL group in GCA analysis. No significance was found in RLSNHL subjects. Additionally, the RSSNHL group showed increased effective connectivity from the right middle frontal gyrus (MFG) and the RLSNHL group showed increased effective connectivity from the right insula and temporal pole to the right cerebellum lobule V. Moreover, connections between right cerebellum lobule V and mean time series of the cerebellar network was negatively correlated with anxiety score in RSSNHL and negatively correlated with depression scores in RLSNHL. Effective connectivity from right MFG to right cerebellum lobule V could predict anxiety status in RSSNHL subjects. Our results may prove potential imaging biomarkers and treatment targets for hearing loss in future work.

Anoctamin 1 Inhibition Suppresses Cystogenesis by Enhancing Ciliogenesis and the Ciliary Dosage of Polycystins.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a ciliopathy characterized by abnormal tubular epithelial proliferation and fluid secretion. Anoctamin 1 (ANO1) is a calcium-dependent chloride channel. However, how ANO1 contributes to ADPKD is largely unexplored. METHODS: Kidney tissues from ADPKD patients, Pkd1RC/RC mice model, WT9-7 human PKD1+⁣/- cells, and 3D culture models in vitro were used. Localization of ANO1 and cilium length were investigated by confocal immunofluorescence. RESULTS: We found that ANO1 was consistently upregulated in human and mouse PKD kidneys. Intriguingly, ANO1 located in a vesicle-like pattern at the ciliary base but not on the ciliary surface. ANO1 deficiency enhanced ciliogenesis and the ciliary dosage of polycystin-2 in human PKD cells, and reduced cyst formation in 3D culture models. Moreover, inhibition of ANO1 abolished the activation of STAT3 and ERK pathways in PKD cells. CONCLUSIONS: Our data indicate ANO1 is a negative regulator for both cilia length and cilia trafficking of polycystin-2 and provide mechanistic insights regarding the therapeutic potential of ANO1 pathway in ADPKD treatment.

Complete regression of xenografted breast tumors by dextran-based dual drug conjugates containing paclitaxel and docosahexaenoic acid.

In this study, a novel carboxymethyl dextran (CMD)-based dual drug delivery system that delivering two water insoluble drugs to tumor sites was developed and evaluated for anticancer activities. Paclitaxel (PTX) and docosahexaenoic acid (DHA) were covalently coupled with CMD to generate CMD-DHA-PTX conjugate S and conjugate L with different linkers containing amino acids Gly-Gly or Lys-Gly-Gly, respectively. Both conjugates possessed high PTX loading contents and enhanced water solubility, as well as the ability of being self-assembled into nanoparticles with the nanoparticle size ranged from 88.7 nm to 94.7 nm. These two conjugates released free PTX continuously in plasma and cancer cells. The conjugate S exhibited improved pharmacokinetic parameters and higher distribution extent in tumor sites than the parent PTX, Abraxane and the conjugate L. The antitumor efficacy of these two conjugates outperformed parent PTX formulation and Abraxane in nude mice bearing breast cancer cells MCF-7. More importantly, the conjugate S treatment eliminated all the xenograft tumors without causing any mice body weight loss in mice model. This study revealed that the dextran-based dual drug conjugates may represent an effective and innovative way to deliver anticancer agents to a variety of tumors.

Reversibility of acute-on-chronic liver failure syndrome in hepatitis B virus-infected patients with and without prior decompensation.

Acute-on-chronic liver failure (ACLF) is a severe clinical syndrome associated with high short-term mortality and reversibility. This study aimed to compare the characteristics of survival and reversibility in hepatitis B virus (HBV)-related ACLF (HBV-ACLF) patients with and without previous decompensation. Overall, 1044 patients who fulfilled the acute hepatic insult criteria of the APASL-ACLF Research Consortium (AARC) definition were enrolled from a prospectively established cohort of HBV-related liver failure patients. These patients were divided into the AARC ACLF group and the non-AARC ACLF group according to prior decompensation. Mortality, reversibility of ACLF syndrome, and predicted factors associated with reversibility were evaluated. Liver transplantation-free mortality of the AARC ACLF group was significantly lower than that of the non-AARC ACLF group (28 days: 28.2% vs. 40.3%, p = .012; 90 days: 41.7% vs. 65.4%, p < .001). The 5-year cumulative reversal rates of ACLF syndrome were 88.0% (374/425) and 66.0% (31/47) in the AARC and non-AARC ACLF groups, respectively, (p = .039). Following reversibility of ACLF syndrome, 340/374 (90.9%) and 21/31 (67.7%) patients in the AARC and non-AARC ACLF groups, respectively, maintained a stable status within 5 years. Although prior decompensation indicated poor reversibility of ACLF syndrome, HBV-infected patients with prior decompensation who fulfilled the acute hepatic insult criteria of the AARC definition showed favourable reversibility and maintained a stable status after receiving nucleoside analogues. The AARC ACLF definition identified HBV-ACLF as a distinct syndrome with good reversibility. HBV-infected patients with prior decompensation could be included in the AARC ACLF management.

Aberrant Functional Network of Small-World in Sudden Sensorineural Hearing Loss With Tinnitus.

Few researchers investigated the topological properties and relationships with cognitive deficits in sudden sensorineural hearing loss (SNHL) with tinnitus. To explore the topological characteristics of the brain connectome following SNHL from the global level and nodal level, we recruited 36 bilateral SNHL patients with tinnitus and 37 well-matched healthy controls. Every subject underwent pure tone audiometry tests, neuropsychological assessments, and MRI scanning. AAL atlas was employed to divide a brain into 90 cortical and subcortical regions of interest, then investigated the global and nodal properties of "small world" network in SNHL and control groups using a graph-theory analysis. The global characteristics include small worldness, cluster coefficient, characteristic path length, local efficiency, and global efficiency. Node properties include degree centrality, betweenness centrality, nodal efficiency, and nodal clustering coefficient. Interregional connectivity analysis was also computed among 90 nodes. We found that the SNHL group had significantly higher hearing thresholds and cognitive impairments, as well as disrupted internal connections among 90 nodes. SNHL group displayed lower AUC of cluster coefficient and path length lambda, but increased global efficiency. The opercular and triangular parts of the inferior frontal gyrus, rectus gyrus, parahippocampal gyrus, precuneus, and amygdala showed abnormal local features. Some of these connectome alterations were correlated with cognitive ability and the duration of SNHL. This study may prove potential imaging biomarkers and treatment targets for future studies.

Primary cilia in satellite cells are the mechanical sensors for muscle hypertrophy.

Skeletal muscle atrophy is commonly associated with aging, immobilization, muscle unloading, and congenital myopathies. Generation of mature muscle cells from skeletal muscle satellite cells (SCs) is pivotal in repairing muscle tissue. Exercise therapy promotes muscle hypertrophy and strength. Primary cilium is implicated as the mechanical sensor in some mammalian cells, but its role in skeletal muscle cells remains vague. To determine mechanical sensors for exercise-induced muscle hypertrophy, we established three SC-specific cilium dysfunctional mouse models-Myogenic factor 5 (Myf5)-Arf-like Protein 3 (Arl3)-/-, Paired box protein Pax-7 (Pax7)-Intraflagellar transport protein 88 homolog (Ift88)-/-, and Pax7-Arl3-/--by specifically deleting a ciliary protein ARL3 in MYF5-expressing SCs, or IFT88 in PAX7-expressing SCs, or ARL3 in PAX7-expressing SCs, respectively. We show that the Myf5-Arl3-/- mice develop grossly the same as WT mice. Intriguingly, mechanical stimulation-induced muscle hypertrophy or myoblast differentiation is abrogated in Myf5-Arl3-/- and Pax7-Arl3-/- mice or primary isolated Myf5-Arl3-/- and Pax7-Ift88-/- myoblasts, likely due to defective cilia-mediated Hedgehog (Hh) signaling. Collectively, we demonstrate SC cilia serve as mechanical sensors and promote exercise-induced muscle hypertrophy via Hh signaling pathway.

The enhanced antitumor activity of the polymeric conjugate covalently coupled with docetaxel and docosahexaenoic acid.

Docetaxel (DTX) has been widely used for the treatment of many types of cancer. However, DTX is poorly water-soluble and commercial DTX is formulated in non-ionic surfactant polysorbate 80 and ethanol, thereby leading to hypersensitivity and serious side effects. Herein, a polymer dual drug conjugate was synthesized by coupling DTX and docosahexaenoic acid (DHA) with bifunctionalized dextran. The polysaccharide conjugate dextran-DHA-DTX possessed high water solubility and was self-assembled into nanoparticles with a diameter of 98.0 ± 6.4 nm. Pharmacokinetic and biodistribution studies showed that the dextran-DHA-DTX dual drug conjugate not only had significantly prolonged blood circulation but was also selectively accumulated in the tumor with reduced drug distribution in normal tissues. The conjugate exhibited a superior therapeutic effect in both xenograft nude mice models without causing any systemic side effects. Notably, the conjugate nearly eliminated all xenograft tumors in nude mice bearing breast cancer cells MCF-7. This study revealed that the dextran-based dual drug delivery system may provide an effective strategy to selectively deliver DTX to tumor sites.