gp120-derived amyloidogenic peptides form amyloid fibrils that increase HIV-1 infectivity.

Apart from mediating viral entry, the function of the free HIV-1 envelope protein (gp120) has yet to be elucidated. Our group previously showed that EP2 derived from one ß-strand in gp120 can form amyloid fibrils that increase HIV-1 infectivity. Importantly, gp120 contains ~30 ß-strands. We examined whether gp120 might serve as a precursor protein for the proteolytic release of amyloidogenic fragments that form amyloid fibrils, thereby promoting viral infection. Peptide array scanning, enzyme degradation assays, and viral infection experiments in vitro confirmed that many ß-stranded peptides derived from gp120 can indeed form amyloid fibrils that increase HIV-1 infectivity. These gp120-derived amyloidogenic peptides, or GAPs, which were confirmed to form amyloid fibrils, were termed gp120-derived enhancers of viral infection (GEVIs). GEVIs specifically capture HIV-1 virions and promote their attachment to target cells, thereby increasing HIV-1 infectivity. Different GAPs can cross-interact to form heterogeneous fibrils that retain the ability to increase HIV-1 infectivity. GEVIs even suppressed the antiviral activity of a panel of antiretroviral agents. Notably, endogenous GAPs and GEVIs were found in the lymphatic fluid, lymph nodes, and cerebrospinal fluid (CSF) of AIDS patients in vivo. Overall, gp120-derived amyloid fibrils might play a crucial role in the process of HIV-1 infectivity and thus represent novel targets for anti-HIV therapeutics.

Factors influencing left ventricular diastolic dysfunction on echocardiography of people living with HIV in Kunming, China.

BACKGROUND: The widespread use of antiretroviral therapy has prolonged the survival of people living with HIV (PLWH). Among these patients, co-existing cardiovascular diseases, particularly left ventricular diastolic dysfunction (LVDD), are receiving increasing attention. METHODS: We recruited 386 patients in the PLWH group and 386 sex- and age (± 3 years)-matched individuals in the HIV-negative group, and used logistic regression to determine the risk factors of LVDD. RESULTS: Compared to the HIV-negative group, PLWH had a significantly higher prevalence of smoking (p < .001), alcohol consumption (p < .001), hypertension (p = .002), diabetes (p = .020), and hyperlipidemia (p < .001) and a lower prevalence of body mass index (BMI) ≥ 24.0 kg/m2 (p < .001). The prevalence of LVDD on echocardiography was significantly higher in PLWH than in the HIV-negative group (25.9% vs 16.1%, p = .001). The multivariate analysis showed that non-youth (OR = 8.666; 95%CI = 4.310-17.459; p < .001), BMI ≥ 24.0 kg/m2 (OR = 1.992; 95% CI = 1.007-3.939; p = .048), hypertension (OR = 1.888; 95% CI = 1.044-3.415; p = .036), hyperlipidemia (OR = 1.911; 95% CI = 1.068-3.418; p = .029), and HIV infection (OR = 2.003; 95%CI = 1.341-2.992; p = .001) were risk factors for LVDD. CONCLUSION: The rate of echocardiographic abnormalities was higher in PLWH. LVDD was associated with non-youth, BMI ≥ 24.0 kg/m2, hypertension, hyperlipidemia, and living with HIV.

Prognostic Factors for Survival of Stage IB Non-small Cell Lung Cancer Patients: A 10-Year Follow-Up Retrospective Study.

BACKGROUND: This study aimed to determine the prognostic factors for the long-term outcome of stage IB non-small cell lung cancer (NSCLC). METHODS: Surgically resected patients with stage IB NSCLC diagnosed (based on TNM 8th edition) between April 2008 and December 2013 were retrospectively reviewed. The prognosis and possible risk factors among the stage IB NSCLC patients were evaluated. RESULTS: Of the 349 patients identified for the study, 80 (22.9%) received post-surgery adjuvant chemotherapy (ACT). The median follow-up time after surgery was 123.3 months. The 10-year overall survival (OS) rate was 69.6%, and the 10-year recurrence-free survival (RFS) rate was 62.8%. The patients in this cohort were divided into three groups (T1 with visceral pleural invasion [VPI], T2a without VPI, and T2a with VPI), and no significant differences in OS or RFS were found among the groups. Furthermore, survival analysis indicated that the absence of ground-glass opacity (GGO) components portends an adverse long-term OS and RFS. In a subgroup of patients with solid nodules, age older than 65 years (hazard ratio [HR] 1.987; 95% confidence interval [CI] 1.312-3.010; p = 0.001) and ACT (HR 0.392; 95% CI 0.225-0.684; p < 0.001) were independent prognostic factors for OS, whereas lymphovascular invasion (HR 1.792; 95% CI 0.995-3.227; p = 0.052) should be considered as an independent unfavorable prognostic factor for RFS. CONCLUSIONS: As an upstaging factor, VPI did not further stratify prognosis for the stage IB patients in our cohort. The presence of GGO components had a notable impact on a favorable prognosis in stage IB NSCLCs.

Long-Term Outcomes of Selected Patients with IIIA-N2 Non-small Cell Lung Cancer Receiving Upfront Surgical Resection.

BACKGROUND: Stage IIIA non-small cell lung cancer (NSCLC) is a diverse group that requires multimodality treatment. The aim of this study was to report the long-term outcomes for patients with IIIA-N2 disease. METHODS: We conducted a retrospective review of cases with IIIA-N2 (T1-2N2) NSCLC who underwent upfront surgery. Kaplan-Meier curves and Cox proportional hazard analyses were used to assess the impact of various variables on survival. RESULTS: A total of 475 patients were ultimately included. With a median follow-up time of 108 months, the 5- and 10-year overall survival (OS) rates were 42.2% and 27.7%, respectively. R0 resection was found to be associated with improved progression-free survival (PFS) and OS compared with R1/R2 resection (p = 0.041 for PFS; p = 0.015 for OS). Patients with single-station N2 disease demonstrated significantly better PFS and OS than those with multiple-station N2 disease (p < 0.001 for PFS; p = 0.002 for OS). Following surgical resection, adjuvant therapy was significantly correlated with prolonged PFS and OS compared with those patients without any treatment. However, there was no significant difference in PFS and OS between chemotherapy and radiochemotherapy (p = 0.915 for PFS; p = 0.287 for OS). Patients with EGFR exon 19 deletion had significantly improved OS compared with those with L858R (p = 0.040). CONCLUSIONS: Our study shows promising long-term outcomes for selected patients with stage IIIA-N2 NSCLC treated with upfront surgery followed by adjuvant therapy, especially those with R0 resection and single-station N2. This study sheds light on the potential management and treatment options for this challenging population.

Carotid Ultrasound Abnormalities of People Living With HIV in Kunming, China: Multiple Correspondence Analysis Approach to Identify Influencing Factors.

BACKGROUND: With the use of antiretroviral therapy (ART), the life expectancy of people living with HIV (PLWH) is gradually increasing, but subclinical atherosclerotic cardiovascular disease is becoming increasingly common in PLWH. METHODS: We obtained data from 326 PLWH. Based on the results of carotid ultrasonography, we divided patients into normal and abnormal carotid ultrasound groups and performed the χ2 test and multiple correspondence analysis (MCA) to determine the influencing factors of abnormal carotid ultrasound. RESULTS: Among the 326 PLWH, the overall abnormality rate of carotid ultrasound was 31.9% (104/326). MCA showed that carotid ultrasound abnormalities were markedly more common in patients with age (non-youth), BMI ≥24.0 kg/m2, hypertension, diabetes, hyperlipidemia, ART treatment ≥5 years, and CD4+T lymphocyte count <200/µL. CONCLUSION: Carotid ultrasound is more likely to be abnormal when PLWH have higher age, BMI ≥24.0 kg/m2, hypertension, diabetes, hyperlipidemia, a longer course of ART, and a low CD4+ T lymphocyte count.

Prognostic effect of ground-glass opacity in subcentimeter invasive lung adenocarcinoma.

Background: Although subcentimeter nodules represent precursor or minimally invasive lung cancer in most cases, there are still a few that are subcentimeter invasive adenocarcinoma (IAC). The aim of this study was to investigate the prognostic effect of ground-glass opacity (GGO) and the optimal surgical procedure in this special group. Methods: Patients with subcentimeter IAC were enrolled and were categorized into pure GGO, part-solid, and solid nodules based on the radiological appearance. Cox proportional hazards model and the Kaplan-Meier method were used for survival analyses. Results: A total of 247 patients were enrolled. Among them, 66 (26.7%) were in the pure-GGO group, 107 (43.3%) were in the part-solid group, and 74 (30.0%) were in the solid group. Survival analysis demonstrated a significantly worse survival in the solid group. Cox multivariate analyses confirmed that the absence of GGO component was an independent risk factor for worse recurrence-free survival (RFS) and overall survival (OS). As for surgical procedures, lobectomy did not provide a significant better RFS or OS than sublobar resection in the whole cohort or in a subgroup of patients with solid nodules. Conclusions: The radiological appearance stratified the prognosis of IAC with size of smaller than or equal to 1 cm. Sublobar resection may be feasible for subcentimeter IAC, even for those appearing as solid nodules; however, caution should be taken when applying wedge resection.

Hydrodynamic simulation of hypervelocity generation by multidimensional graded impactors: Planarity enhancement study.

Hypervelocity impact in the universe can be generated by a three-stage gas gun. Achieving the desirable planarity of the flyer enlarges the experimentally effective area of the flyer under the hypervelocity condition. The multidimensional graded density impactor (MDGDI) enhances the planarity of the flyer. In this investigation, a one-dimensional Lagrange elastoplastic hydrodynamic method and a Euler grid finite difference method were used to examine the relationship between the structure of graded density impactors (GDIs) and the planarity of flyers. MDGDIs lead to a deviation of the stress wave produced by the one-dimensional graded density impactor (1DGDI), which offsets the stress disturbance effect, changes the velocity at each particle, and enhances the planarity of flyers. The proportion of flat areas of the flyer increases from 52.70% to 95.71% by adopting MDGDIs. The proportion of flat areas is linear with the wave impedance of the high-impedance layer for 1DGDIs and the wave impedance near the barrel of the high-impedance layer for MDGDIs. This investigation guides the design of GDIs and expands the application of gas gun technology in the field of hypervelocity impact.

Excellent survival of pathological N0 small cell lung cancer patients following surgery.

BACKGROUND: Current clinical guidelines recommend surgery only for cT1-2N0M0 small cell lung cancer (SCLC) patients. In light of recent studies, the role of surgery in the treatment of SCLC needs to be reconsidered. METHODS: We reviewed all SCLC patients who underwent surgery from November 2006 to April 2021. Clinicopathological characteristics were retrospectively collected from medical records. Survival analysis was performed by the Kaplan-Meier method. Independent prognostic factors were evaluated by Cox proportional hazard model. RESULTS: 196 SCLC patients undergoing surgical resection were enrolled. The 5-year overall survival for the entire cohort was 49.0% (95% CI: 40.1-58.5%). PN0 patients had significantly superior survival to pN1-2 patients (p < 0.001). The 5-year survival rate of pN0 and pN1-2 patients were 65.5% (95% CI: 54.0-80.8%) and 35.1% (95% CI: 23.3-46.6%), respectively. Multivariate analysis revealed that smoking, older age, and advanced pathological T and N stages were independently associated with poor prognosis. Subgroup analyses demonstrated similar survival among pN0 SCLC patients regardless of pathological T stages (p = 0.416). Furthermore, multivariate analysis showed factors, including age, smoking history, type of surgery, and range of resection, were not independently prognostic factors for the pN0 SCLC patients. CONCLUSION: Pathological N0 stage SCLC patients have significantly superior survival to pN1-2 patients, regardless of features, including T stage. Thorough preoperative evaluation should be applied to estimate the status of lymph node involvement to achieve better selection of patients who might be candidate for surgery. Studies with larger cohort might help verify the benefit of surgery, especially for T3/4 patients.

Impact of Prior Cancer History on Outcomes of Resected Lung Cancer.

BACKGROUND: Previous studies concerning the impact of prior cancer on newly diagnosed lung cancer are mainly based on databases and obtained mixed results. Utilizing a large study population, we aimed to reveal this impact. PATIENTS AND METHODS: Lung cancer patients from January 2008 to April 2021 were enrolled. The Kaplan-Meier method was used to perform survival analyses. To investigate the impact of prior cancer, a Cox proportional hazards model was conducted. To minimize the influence of the heterogeneity of prior cancer, stratified analyses were carried out. RESULTS: In total, 17,423 lung cancer patients were reviewed, among which we identified 1469 (8.4%) patients with a history of prior cancer. Cox regression analysis revealed that prior cancer was an independent poor prognostic factor on overall survival (HR = 1.430, 95% CI: 1.147-1.784, p = 0.001) but did not affect lung cancer-specific survival (HR = 1.120, 95% CI: 0.876-1.434, p = 0.366). Interestingly, in further stratified analyses, we found that prior cancer history affected overall survival only in pTNM stage 0/I patients (HR = 1.670, 95% CI: 1.247-2.237, p = 0.001), but not in pTNM stage II/III/IV patients (HR = 1.237, 95% CI: 0.877-1.743, p = 0.226). Similarly, prior cancer was an independent poor prognostic factor on overall survival only for pN0 patients. Subsequently, subgroup analyses indicated that the impact of prior cancer varied in pTNM stage 0/I patients according to the type of prior cancer and the interval time. CONCLUSIONS: Considering that prior cancer affects overall survival in patients with clinically curable lung cancer, clinicians should pay attention to this effect and improve the management of these patients to achieve a better prognosis.

Pregnancy may have little influence on ground-glass opacities suspected for lung adenocarcinoma.

PURPOSE: Owing to the popularity of low-dose computed tomography in lung cancer screening, young women spotted with ground-glass opacities (GGO) is a growing subgroup in clinical practice. We aim to investigate the influence of pregnancy on GGOs suspected for lung adenocarcinoma. METHODS: This retrospective study collected a series of female patients who were pregnant in follow-up of GGO lesions. The last CT images of GGO before pregnancy (CT1) and the first CT images after pregnancy (CT2) were reviewed to assess any radiologic change. Young female patients who were not pregnant in long-term (> 12 months) follow-up of GGO were enrolled as a comparison group. We also enrolled patients who gave birth within 2 years before surgical resection of GGOs. RESULTS: Four patients were enrolled according to the criteria. There was no significant change of the GGOs in all four patients with a median follow-up duration of 45.5 (range 17-86) months. Two patients were diagnosed pathologically to be minimally invasive adenocarcinoma, one was invasive adenocarcinoma and one did not underwent surgery. Six patients were enrolled in the comparison group and no significant change was witnessed in all the nodules. In those patients who gave birth within two years before surgical resection of GGOs, we found that the majority present as preinvasive lesions, and those with invasive adenocarcinomas were bigger in size and possess more solid component radiologically. CONCLUSION: Pregnancy seems to have little impact on GGOs suspected for lung adenocarcinoma. Therefore, pregnancy might be safely planned during the follow-up of GGOs.

Clinical characteristics and progression of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET rearrangements: a retrospective cohort study.

Background: Patients harboring anaplastic lymphoma kinase (ALK) or rearranged during transfection (RET) rearrangements are usually diagnosed at a relatively late stage with nodal and distant metastasis, and rapid progression course of ALK/RET fusion-positive lung cancer were well-known. However, clinical characteristics and course of pre-/minimally invasive lung adenocarcinoma harboring ALK or RET fusions are poorly described. Identifying patients with gene fusions at early stage may offer surgical options that could cure those patients. Methods: We retrospectively included patients with surgically resected pre-/minimally invasive lung adenocarcinomas harboring epidermal growth factor receptor (EGFR) mutations or ALK/RET rearrangements, and further compared the patient clinical characteristics, nodule natural course, and survival outcomes. Radiological characteristics including ground-glass component, cystic airspace, pleural attachment, etc. were specially assessed for this study. EGFR (exons 18-22) was detected by Sanger sequencing and quantitative real-time polymerase chain reaction (qRT-PCR) was used to analyze the ALK/RET rearrangements. Lung cancer-specific survival (LCSS), relapse-free survival (RFS), and overall survival (OS) were all evaluated. Results: Of 238 patients with pre-/minimally invasive lung adenocarcinomas, 226 patients had EGFR mutations, 7 patients had ALK fusions, and 5 patients had RET fusions. Average age at surgery was 45.3 years for ALK/RET-positive group and 52.6 years for EGFR-positive group (P=0.049). Radiologically, among the 12 patients with ALK/RET fusions, the majority of lesions (10/12) manifested as mixed ground-glass opacities (mGGOs), which was significantly more prevalent when compared with patients with EGFR mutations (83.4% vs. 24.3%, P<0.001). Moreover, a substantial proportion of cystic airspace was found in ALK/RET-positive group but not in EGFR-positive group (66.7% vs. 14.2%, P<0.001). Among four patients with ALK/RET fusions undergoing surveillance over 1 year before surgery, two of them developed rapid radiologic progression. The 5-year LCSS and RFS were 100%, 100% for ALK/RET-positive group, and 100%, 100% for EGFR-positive group, respectively. Conclusions: ALK/RET-positive pre-/minimally invasive lung adenocarcinomas were mostly characterized as mGGOs with cystic airspace developing rapid nodule progression, and no recurrence occurred during long-term follow-up after resection. This provides insights into proper curative surgery timing in the management of patients with gene fusions. However, these findings must be treated with caution and validated in future multi-center studies with larger sample size.

Potential of blood exosomal ENAH, SEPT9, EGF, MMP-9 and CXCL8 for the early screening of breast cancer.

Exosomal contents have been recognized as candidate biomarkers for cancer screening and prognosis. The current study aimed to evaluate the potential of the expression levels of exosomal enabled homolog (ENAH), septin 9 (SEPT9), epidermal growth factor (EGF), matrix metalloproteinase-9 (MMP-9) and C-X-C motif chemokine ligand 8 (CXCL8) in the blood for the early screening of breast cancer. Therefore, exosomes were extracted and purified from the peripheral blood of 47 patients with breast cancer, 63 disease controls (DCs) and 33 healthy controls (HCs). Subsequently, the exosomal mRNA expression levels of ENAH, SEPT9, EGF, MMP-9 and CXCL8 were detected by reverse transcription-quantitative polymerase chain reaction. The results showed that the exosomal levels of ENAH and EGF were significantly higher in patients with breast cancer compared with DCs and HCs (both P<0.001). In addition, receiver operating characteristic curves revealed that exosomal ENAH was able to discriminate patients with breast cancer from DCs [area under the curve (AUC), 0.841] and HCs (AUC, 0.859). However, exosomal EGF was only able to discriminate patients with breast cancer from HCs (AUC, 0.776). Furthermore, the levels of exosomal SEPT9 were lower in patients with breast cancer compared with DCs and HCs (P=0.021), and exosomal SEPT9 expression levels exhibited good potential in the discrimination of patients with breast cancer from DCs (AUC, 0.717) and HCs (AUC, 0.830). However, no significant difference was detected in exosomal levels of MMP-9 and CXCL8 among the three groups, and these RNAs showed no discriminative ability. In addition, in patients with breast cancer, the exosomal levels of ENAH were associated with molecular subtypes (P=0.010), while those of MMP-9 were associated with a Ki-67 index of ≥30% (P=0.011). In conclusion, the exosomal levels of ENAH, SEPT9 and EGF in blood samples were able to identify patients with breast cancer, thus providing a novel approach for the early screening of breast cancer.

Comprehensive analysis of mutational profile and prognostic significance of complex glandular pattern in lung adenocarcinoma.

Background: Complex glandular pattern (CGP) was included as high-grade pattern in the new grading system proposed by The International Association for the Study of Lung Cancer. We aimed to investigate the mutational profile and validate the prognostic significance and proper cut-off value to distinguish the aggressive behavior of CGP. Methods: CGP was defined as nests of tumor cells with sieve-like perforation, fused glands with irregular borders or back-to-back glands without intervening stroma. Patients were categorized into four groups according to the percentage of CGP component (0%, 1-19%, 20-49%, 50-100%). Cox's proportional hazards model was applied to analyze recurrence free survival (RFS) and overall survival (OS). Results: A total of 950 patients with resected lung adenocarcinoma was enrolled. The most frequent driver mutation in this cohort was EGFR and was detected in 624 (65.7%) patients. EGFR mutation was more frequently observed in patients with <20% CGP than in patients with ≥20% CGP (73.6% vs. 60.2%), while KRAS mutation and ALK rearrangement was significantly associated with ≥20% CGP. Patients with 20% or greater CGP exhibited significant worse RFS (P<0.001) and OS (P<0.001) than their counterparts. Moreover, the multivariate Cox regression analysis confirmed that CGP (≥20%) was a risk factor for a worse RFS (P=0.001) and OS (P<0.001) independent of staging and gene mutation. Smaller portion of CGP (<20%) were comparable in RFS and OS to those without CGP (0%). There was also no significant difference in RFS and OS between the 20-49% and ≥50% group. Conclusions: Our study provided mutational profile of patients with different CGP, validated CGP as a negative prognostic factor and provided extra evidences for the optimal cut-off value of CGP percentage.

Cytomegalovirus viremia is associated with poor outcomes in AIDS patients with disseminated nontuberculous mycobacterial disease.

Both cytomegalovirus (CMV) viremia and disseminated nontuberculous mycobacterial (NTM) disease are common opportunistic infections in AIDS patients. Whether concurrent CMV viremia is associated with mortality in patients with AIDS and disseminated NTM disease is unknown. Subjects were patients with AIDS and disseminated NTM disease seen at a single center from January 2015 to April 2021. Data were retrospectively collected. Differences in demographics and clinical characteristics and hospitalization survival rates were compared between patients with disseminated NTM and with CMV viremia or not. Subjects were 113 AIDS patients with disseminated NTM who were seen at this Hospital from January 2015 to April 2021. Twenty-six of the patients had CMV viremia and 87 did not. The median age was 36 years (interquartile range [IQR] 29-42) and 108 patients were male (96%). The median CD4 count was 7 cells/µL (IQR 3-17). The median plasma CMV viral load was 9,245 IU/mL (IQR 3147-45725). The serum albumin of patients with CMV viremia was significantly lower than that of patients without CMV viremia (P = 0.03). Compared to patients without CMV viremia (81.6%), patients with CMV viremia had a significantly poorer prognosis (P = 0.01). Cox regression analysis indicated that the risk of a poor prognosis in patients with CMV viremia was 4.7 times higher than that in patients without CMV viremia (P = 0.003), and patients with CD8 more than 250/µL had a better prognosis (P = 0.02). CMV viremia increases the risk of a poor prognosis in patients with AIDS and a disseminated NTM infection. A routine CMV DNA test should be performed on patients with AIDS and disseminated NTM disease in order to reduce the risk of death.

A Real-world Evidence-based Management of HIV by Differential Duration HAART Treatment and its Association with Incidence of Oral Lesions.

BACKGROUND: The efficacy of highly active antiretroviral therapy (HAART) can be estimated by the immunological response and the incidence of opportunistic infections. OBJECTIVE: This study aimed at evaluating the effectiveness of different durations of HAART in terms of immunological response markers (CD4 count and CD4/CD8 ratio) along with disease progression markers (incidence of oral lesions) in Chinese patients with HIV. METHODS: This single-center, retrospective, and real-world study included patients with HIV, grouped into a treatment group and treatment-naïve group, of which the former was further divided into 6, 12, and 18 months based on the treatment duration. The CD4 and CD8 cell counts were analyzed by the FACSCalibur flow cytometry. Kruskal-Wallis test was applied to determine the outcome of different duration of HAART. Oral examination was carried out according to the WHO type IV examination. RESULTS: In 246 patients with HIV, CD4 counts increased significantly post-HAART compared to pre-HAART in all three treatment groups (P<.001), while CD8 count decreased significantly (P<.05) in all three treated groups. A significant association of HAART with the CD4/CD8 ratio was observed (P<.001). A significant increase in CD4 count was observed between 12-months and 18-months treatment groups (P<.05). The occurrence of oral lesions reduced significantly in the treatment group. CONCLUSION: We observed a better response to the HAART regimen with 18-months of duration than 12-months and 6-months therapies and reduction in oral lesions.

Excessive mechanical strain accelerates intervertebral disc degeneration by disrupting intrinsic circadian rhythm.

Night shift workers with disordered rhythmic mechanical loading are more prone to intervertebral disc degeneration (IDD). Our results showed that circadian rhythm (CR) was dampened in degenerated and aged NP cells. Long-term environmental CR disruption promoted IDD in rats. Excessive mechanical strain disrupted the CR and inhibited the expression of core clock proteins. The inhibitory effect of mechanical loading on the expression of extracellular matrix genes could be reversed by BMAL1 overexpression in NP cells. The Rho/ROCK pathway was demonstrated to mediate the effect of mechanical stimulation on CR. Prolonged mechanical loading for 12 months affected intrinsic CR genes and induced IDD in a model of upright posture in a normal environment. Unexpectedly, mechanical loading further accelerated the IDD in an Light-Dark (LD) cycle-disrupted environment. These results indicated that intrinsic CR disruption might be a mechanism involved in overloading-induced IDD and a potential drug target for night shift workers.