Sex differences in default mode network connectivity in healthy aging adults.

Women show an increased lifetime risk of Alzheimer's disease (AD) compared with men. Characteristic brain connectivity changes, particularly within the default mode network (DMN), have been associated with both symptomatic and preclinical AD, but the impact of sex on DMN function throughout aging is poorly understood. We investigated sex differences in DMN connectivity over the lifespan in 595 cognitively healthy participants from the Human Connectome Project-Aging cohort. We used the intrinsic connectivity distribution (a robust voxel-based metric of functional connectivity) and a seed connectivity approach to determine sex differences within the DMN and between the DMN and whole brain. Compared with men, women demonstrated higher connectivity with age in posterior DMN nodes and lower connectivity in the medial prefrontal cortex. Differences were most prominent in the decades surrounding menopause. Seed-based analysis revealed higher connectivity in women from the posterior cingulate to angular gyrus, which correlated with neuropsychological measures of declarative memory, and hippocampus. Taken together, we show significant sex differences in DMN subnetworks over the lifespan, including patterns in aging women that resemble changes previously seen in preclinical AD. These findings highlight the importance of considering sex in neuroimaging studies of aging and neurodegeneration.

Anatomic identification of laparoscopic uterosacral ligament suspension: A step-by-step procedure.

INTRODUCTION AND HYPOSTHESIS: The uterosacral ligament (USL) is the main structure of physiological apical support, and USL suspension is one of the most commonly used methods for native tissue apical suspension. Structures surrounding the USL are complex, and the USL itself is difficult to identify, especially the sacral portion of the USL. Laparoscopy improves visualization, but exposure of the USL is still unsatisfactory. METHODS: In this study, we report a simple method for exposing and suturing the USL laparoscopically, with step-by-step instructions, well-presented figures and videos. The key techniques are shown as follows: keeping tension on the USL with a uterine manipulator, dissecting the space medial to the USL, exposing the portion of the USL near the sacrum through the natural space, and then suturing it medially and connecting it directly to the posterior cervix. RESULTS: 95 consecutive patients have undergone this modified USLS and none had serious perioperative complication. CONCLUSION: In this way, the USL anatomy is exposed well, which may make placement of sutures in USL suspension safe and effective.

Ritonavir-boosted indinavir but not lopinavir inhibits erythrocytic stage Plasmodium knowlesi malaria in rhesus macaques.

The inhibitive activities of the human immunodeficiency virus protease inhibitors ritonavir (RTV) boosted indinavir (IDV) and RTV boosted lopinavir (LPV) for erythrocytic stage malaria were evaluated in rhesus macaques. The IDV/RTV regimen effectively inhibits the replication of Plasmodium knowlesi with clinically relevant doses, whereas the LPV/RTV regimen did not show activity against plasmodium infection.

Evaluation of spiropiperidine hydantoins as a novel class of antimalarial agents.

Given the rise of parasite resistance to all currently used antimalarial drugs, the identification of novel chemotypes with unique mechanisms of action is of paramount importance. Since Plasmodium expresses a number of aspartic proteases necessary for its survival, we have mined antimalarial datasets for drug-like aspartic protease inhibitors. This effort led to the identification of spiropiperidine hydantoins, bearing similarity to known inhibitors of the human aspartic protease ß-secretase (BACE), as new leads for antimalarial drug discovery. Spiropiperidine hydantoins have a dynamic structure-activity relationship profile with positions identified as being tolerant of a variety of substitution patterns as well as a key piperidine N-benzyl phenol pharmacophore. Lead compounds 4e (CWHM-123) and 12k (CWHM-505) are potent antimalarials with IC50 values against Plasmodium falciparum 3D7 of 0.310 µM and 0.099 µM, respectively, and the former features equivalent potency on the chloroquine-resistant Dd2 strain. Remarkably, these compounds do not inhibit human aspartic proteases BACE, cathepsins D and E, or Plasmodium plasmepsins II and IV despite their similarity to known BACE inhibitors. Although the current leads suffer from poor metabolic stability, they do fit into a drug-like chemical property space and provide a new class of potent antimalarial agents for further study.

Plasmodium infection reduces the volume of the viral reservoir in SIV-infected rhesus macaques receiving antiretroviral therapy.

BACKGROUND: Previous studies indicated that Plasmodium infection activates the immune system, including memory CD4+ T cells, which constitute the reservoir of human immunodeficiency virus type-1 (HIV-1). Therefore, we postulated that co-infection with malaria might activate the reservoir of HIV-1. To test this hypothesis, we used a rhesus macaque model of co-infection with malaria and simian immunodeficiency virus (SIV), along with antiretroviral therapy (ART). RESULTS: Our results showed that Plasmodium infection reduced both the replication-competent virus pool in resting CD4+ T cells and the integrated virus DNA (iDNA) load in peripheral blood mononuclear cells in the monkeys. This reduction might be attributable to malaria-mediated activation and apoptotic induction of memory CD4+ T cells. Further studies indicated that histone acetylation and NF-kappaB (NF-κB) activation in resting CD4+ T cells may also play an important role in this reduction. CONCLUSIONS: The findings of this work expand our knowledge of the interaction between these two diseases. As more HIV-1-infected individuals in malaria-endemic areas receive ART, we should explore whether any of the patients co-infected with Plasmodium experience virologic benefits.

Medial amygdalar tau is associated with anxiety symptoms in preclinical Alzheimer's disease.

BACKGROUND: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODS: We examined n=598 individuals (n=347 amyloid-positive (58% female), n=251 amyloid-negative (62% female); subset into tau PET and fMRI cohorts) from the A4 Study. In our tau PET cohort, we used amygdalar segmentations to examine representative nuclei from three functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the fMRI cohort. Finally, we conducted exploratory post-hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTS: Amyloid-positive individuals demonstrated increased tau binding in medial and lateral amygdala (F(4,442)=14.61, p=0.00045; F(4,442)=5.83, p=0.024, respectively). Across amygdalar divisions, amyloid-positive individuals had relatively increased regional connectivity from amygdala to other temporal regions, insula, and orbitofrontal cortex. There was an interaction by amyloid group between tau binding in the medial and lateral amygdala and anxiety. Medial amygdala to retrosplenial connectivity negatively correlated with anxiety symptoms (rs=-0.103, p=0.015). CONCLUSIONS: Our findings suggest that preclinical tau deposition in the amygdala may result in meaningful changes in functional connectivity which may predispose patients to mood symptoms.

Medial Amygdalar Tau Is Associated With Mood Symptoms in Preclinical Alzheimer's Disease.

BACKGROUND: While the amygdala receives early tau deposition in Alzheimer's disease (AD) and is involved in social and emotional processing, the relationship between amygdalar tau and early neuropsychiatric symptoms in AD is unknown. We sought to determine whether focal tau binding in the amygdala and abnormal amygdalar connectivity were detectable in a preclinical AD cohort and identify relationships between these and self-reported mood symptoms. METHODS: We examined 598 individuals (347 amyloid positive [58% female], 251 amyloid negative [62% female] subset in tau positron emission tomography and functional magnetic resonance imaging cohorts) from the A4 (Anti-Amyloid Treatment in Asymptomatic AD) Study. In the tau positron emission tomography cohort, we used amygdalar segmentations to examine representative nuclei from 3 functional divisions of the amygdala. We analyzed between-group differences in division-specific tau binding in the amygdala in preclinical AD. We conducted seed-based functional connectivity analyses from each division in the functional magnetic resonance imaging cohort. Finally, we conducted exploratory post hoc correlation analyses between neuroimaging biomarkers of interest and anxiety and depression scores. RESULTS: Amyloid-positive individuals demonstrated increased tau binding in the medial and lateral amygdala, and tau binding in these regions was associated with mood symptoms. Across amygdalar divisions, amyloid-positive individuals had relatively higher regional connectivity from the amygdala to other temporal regions, the insula, and the orbitofrontal cortex, but medial amygdala to retrosplenial cortex connectivity was lower. Medial amygdala to retrosplenial connectivity was negatively associated with anxiety symptoms, as was retrosplenial tau. CONCLUSIONS: Our findings suggest that preclinical tau deposition in the amygdala and associated changes in functional connectivity may be related to early mood symptoms in AD.

Improving suicide risk prediction via targeted data fusion: proof of concept using medical claims data.

OBJECTIVE: Reducing suicidal behavior among patients in the healthcare system requires accurate and explainable predictive models of suicide risk across diverse healthcare settings. MATERIALS AND METHODS: We proposed a general targeted fusion learning framework that can be used to build a tailored risk prediction model for any specific healthcare setting, drawing on information fusion from a separate more comprehensive dataset with indirect sample linkage through patient similarities. As a proof of concept, we predicted suicide-related hospitalizations for pediatric patients in a limited statewide Hospital Inpatient Discharge Dataset (HIDD) fused with a more comprehensive medical All-Payer Claims Database (APCD) from Connecticut. RESULTS: We built a suicide risk prediction model for the source data (APCD) and calculated patient risk scores. Patient similarity scores between patients in the source and target (HIDD) datasets using their demographic characteristics and diagnosis codes were assessed. A fused risk score was generated for each patient in the target dataset using our proposed targeted fusion framework. With this model, the averaged sensitivities at 90% and 95% specificity improved by 67% and 171%, and the positive predictive values for the combined fusion model improved 64% and 135% compared to the conventional model. DISCUSSION AND CONCLUSIONS: We proposed a general targeted fusion learning framework that can be used to build a tailored predictive model for any specific healthcare setting. Results from this study suggest we can improve the performance of predictive models in specific target settings without complete integration of the raw records from external data sources.

Digital Cell Atlas of Mouse Uterus: From Regenerative Stage to Maturational Stage.

Endometrium undergoes repeated repair and regeneration during the menstrual cycle. Previous attempts using gene expression data to define the menstrual cycle failed to come to an agreement. Here we used single-cell RNA sequencing data of C57BL/6J mice uteri to construct a novel integrated cell atlas of mice uteri from the regenerative endometrium to the maturational endometrium at the single-cell level, providing a more accurate cytological-based elucidation for the changes that occurred in the endometrium during the estrus cycle. Based on the expression levels of proliferating cell nuclear antigen, differentially expressed genes, and gene ontology terms, we delineated in detail the transitions of epithelial cells, stromal cells, and immune cells that happened during the estrus cycle. The transcription factors that shaped the differentiation of the mononuclear phagocyte system had been proposed, being Mafb, Irf7, and Nr4a1. The amounts and functions of immune cells varied sharply in two stages, especially NK cells and macrophages. We also found putative uterus tissue-resident macrophages and identified potential endometrial mesenchymal stem cells (high expression of Cd34, Pdgfrb, Aldh1a2) in vivo. The cell atlas of mice uteri presented here would improve our understanding of the transitions that occurred in the endometrium from the regenerative endometrium to the maturational endometrium. With the assistance of a normal cell atlas as a reference, we may identify morphologically unaffected abnormalities in future clinical practice. Cautions would be needed when adopting our conclusions, for the limited number of mice that participated in this study may affect the strength of our conclusions.

Finite-size scaling of O(n) systems at the upper critical dimensionality.

Logarithmic finite-size scaling of the O(n) universality class at the upper critical dimensionality (d c = 4) has a fundamental role in statistical and condensed-matter physics and important applications in various experimental systems. Here, we address this long-standing problem in the context of the n-vector model (n = 1, 2, 3) on periodic four-dimensional hypercubic lattices. We establish an explicit scaling form for the free-energy density, which simultaneously consists of a scaling term for the Gaussian fixed point and another term with multiplicative logarithmic corrections. In particular, we conjecture that the critical two-point correlation g(r, L), with L the linear size, exhibits a two-length behavior: follows [Formula: see text] governed by the Gaussian fixed point at shorter distances and enters a plateau at larger distances whose height decays as [Formula: see text] with [Formula: see text] a logarithmic correction exponent. Using extensive Monte Carlo simulations, we provide complementary evidence for the predictions through the finite-size scaling of observables, including the two-point correlation, the magnetic fluctuations at zero and nonzero Fourier modes and the Binder cumulant. Our work sheds light on the formulation of logarithmic finite-size scaling and has practical applications in experimental systems.

Impact on lower limb lymphedema of pelvic lymphadenectomy with external iliac lymph nodes left-opened distal lymphatics technique.

BACKGROUND: The aim of this study was to investigate the effect of maintaining opened distal lymphatic vessels of external iliac lymph nodes on lymphedema and lymphocyst formation of lower limbs after pelvic lymphadenectomy. METHODS: Prospective single center observational study was carried out in 83 patients with gynecological malignancies who underwent pelvic lymphadenectomy. During the operation, the distal lymphatic vessels of the external iliac lymph nodes were cut off by an ultrasound scalpel or scissors, and the proximal end was closed by bipolar coagulation. The patients were re-examined by a physical examination, ultrasound examination and inquiry of the symptoms within 2 years after the operation to check whether they had lower limb lymphedema and to analyze the presence of lymphedema and lymphocyst of lower limbs and the risk. RESULTS: The incidence of lower limb lymphedema (LLL) was 21.6% (18/83). Among the patients with LLL, 5.5% (1/18) was diagnosed with stage 0 according to the criteria of International Society of Lymphology, 83.3% (15/18) with stage 1, and 11.1% (2/18) with stage 2. Presently, there was no lymphedema diagnosed at stage 3. The incidence of lymphocyst was 7.2% (6/83). Among the patients with lymphocyst, 3.6% (3/83) occurred 1 month after operation, 2.4% (2/83) occurred 3 months after operation and 1.2% (1/83) occurred 6 months after operation. Patients with radiotherapy and abdominal infection were more likely to suffer from LLL (P<0.05). CONCLUSIONS: Maintaining opened distal lymphatic vessels of external iliac lymph nodes during pelvic lymphadenectomy is feasible, safe and with a 21.6% and 7.2% of potential lymphedema and lymphocists, respectively.

Ischemia Reperfusion Injury after Gradual versus Rapid Flow Restoration for Middle Cerebral Artery Occlusion Rats.

Ischemia-reperfusion injury (IRI) is an important cause of adverse prognosis after recanalization in patients with acute occlusion of major intracranial artery (AOMIA). Here, we provided data indicating that gradual flow restoration (GFR) would be superior to rapid flow restoration (RFR) in alleviating cerebral IRIs in middle cerebral artery occlusion (MCAO) rats. A total of 94 MCAO rats with 15, 30 and 60-minute occlusion were randomly assigned to receive either GFR or RFR intervention. There were significant differences between GFR and RFR group in mean neurological severity score (1.02 versus 1.28; p < 0.05), median infarct ratio (0.016 versus 0.12; p < 0.001), median neuronal apoptosis ratio (1.81 versus 14.46; p < 0.001), and mean histopathological abnormality score (0.92 versus 1.66; p < 0.001). In addition, these differences were mainly distributed in 30-minute and 60-minute occlusion rats, not in 15-minute occlusion rats. These results indicated that GFR rather than RFR could effectively alleviate cerebral IRIs in MCAO rats, especially in rats with longer occlusion duration, suggesting that GFR may be particularly applicable to AOMIA patients who are presented to neurointerventionalists in the later-time of recanalization therapy window.

Comparative data on SD-OCT for the retinal nerve fiber layer and retinal macular thickness in a large cohort with Marfan syndrome.

PURPOSE: To report the distribution of macular and optic nerve topography in the eyes of individuals with Marfan syndrome aged 8-56 years using spectral domain optical coherence tomography (SD-OCT). METHODS: Thirty-three patients with Marfan syndrome underwent a full eye examination including slit-lamp biomicroscopy, indirect ophthalmoscopy, and axial length measurement; and SD-OCT measurements of the retinal nerve fiber layer (RNFL) and macular thickness. RESULTS: For patients between the ages of 8 and 12 years, the average RNFL thickness is 98 ± 9 µm, the vertical cup to disc (C:D) ratio is 0.50 ± 0.10, the central subfield thickness (CST) is 274 ± 38 µm, and the macular volume is 10.3 ± 0.6 mm3. For patients between the ages of 13 and 17 years, the average RNFL is 86 ± 16 µm, the vertical C:D ratio is 0.35 ± 0.20, the CST is 259 ± 15 µm, and the macular volume is 10.1 ± 0.5 mm3. For patients 18 years or older, the average RNFL is 89 ± 12 µm, the vertical C:D ratio is 0.46 ± 0.18, the CST is 262 ± 20 µm, and the macular volume is 10.2 ± 0.4 mm3. When the average RNFL data are compared to a normative, age-adjusted database, 6 of 33 (18%) were thinner than the 5% limit. CONCLUSION: This study reports the distribution of SD-OCT data for patients with Marfan syndrome. Compared to a normative database, 18% of eyes with Marfan syndrome had RNFL thickness < 5% of the population.

Physapubescin B inhibits tumorgenesis and circumvents taxol resistance of ovarian cancer cells through STAT3 signaling.

Ovarian cancer is the most lethal gynaecological malignancy. Recurrence and subsequent resistance to chemotherapy have become major obstacles to treating these diseases. In the present study, we showed that a natural withanolide isolated from the plant Physalis pubescens L. (Solanaceae), Physapubescin B, exhibited potent anti-tumor activity against ovarian cancer cells. Physapubescin B promoted apoptosis, induced cell-cycle arrest and inhibited invasion of ES-2 and A2780 cells. Physapubescin B treatment also resulted in suppression of the transcriptional activity of STAT3, an oncogenic transcription factor activated in many human malignancies including ovarian cancer, through disturbing the dimerization of STAT3, and thereby inhibited the nuclear translocation of Tyr705/Ser727-phosphorylated STAT3. The IL-6-stimulated activation of STAT3 and its downstream genes Cyclin D1, survivin, and Bcl-xL was also repressed by Physapubescin B. Furthermore, Physapubescin B sensitizes A2780 cells to taxol-induced cell growth inhibition in vitro. These findings strongly suggest that Physapubescin B has potential antitumor activity and may circumvent taxol resistance in human ovarian cancer cells through inhibition of aberrant activation of STAT3.

Prevalence and genotype distribution of human papillomavirus in 961,029 screening tests in southeastern China (Zhejiang Province) between 2011 and 2015.

Human papillomavirus infection plays a key role in the development of cervical cancer. To establish a foundation for HPV-based screening and vaccination programs, we investigated the HPV prevalence and genotypic distributions in Chinese women from Zhejiang Province. Between 2011 and 2015, a total of 961,029 samples from 2021 clinical hospitals were tested HPV genotype by a PCR-based hybridization gene chip assay, and 443,890 samples were evaluated cervical cytology by liquid-based cytology analysis. Our results showed that the positive rate for HPV was 20.54%, which ranged from 28.72% to 17.81% and varied by year of recruitment. Age-specific prevalence showed a "two-peak" pattern, with the ≤20-year-old group presenting the highest HPV infection rate, followed by 61-70-year-old group. Overall, the most prevalent genotypes were HPV16, 52 and 58. Additionally, the odds ratios for the prevalence of the HR-HPV, LR-HPV and HPV-negative groups with abnormal cytology were 12.56, 3.21 and 0.06, respectively. Among genotypes, HPV 16 has been found to have the highest OR, followed by HPV58, 18, 52. Here, we present data regarding the prevalence and type distribution of HPV infection, which can serve as valuable reference to guide nationwide cervical cancer screening and HPV vaccination programs.

Evaluation of aminohydantoins as a novel class of antimalarial agents.

Given the threat of drug resistance, there is an acute need for new classes of antimalarial agents that act via a unique mechanism of action relative to currently used drugs. We have identified a set of druglike compounds within the Tres Cantos Anti-Malarial Set (TCAMS) which likely act via inhibition of a Plasmodium aspartic protease. Structure-activity relationship analysis and optimization of these aminohydantoins demonstrate that these compounds are potent nanomolar inhibitors of the Plasmodium aspartic proteases PM-II and PM-IV and likely one or more other Plasmodium aspartic proteases. Incorporation of a bulky group, such as a cyclohexyl group, on the aminohydantion N-3 position gives enhanced antimalarial potency while reducing inhibition of human aspartic proteases such as BACE. We have identified compound 8p (CWHM-117) as a promising lead for optimization as an antimalarial drug with a low molecular weight, modest lipophilicity, oral bioavailability, and in vivo antimalarial activity in mice.

Targeted genome engineering in human induced pluripotent stem cells by penetrating TALENs.

BACKGROUND: Zinc-finger nucleases (ZFNs) and transcription activator-like effector nucleases (TALENs) have been successfully used to knock out endogenous genes in stem cell research. However, the deficiencies of current gene-based delivery systems may hamper the clinical application of these nucleases. A new delivery method that can improve the utility of these nucleases is needed. RESULTS: In this study, we utilized a cell-penetrating peptide-based system for ZFN and TALEN delivery. Functional TAT-ZFN and TAT-TALEN proteins were generated by fusing the cell-penetrating TAT peptide to ZFN and TALEN, respectively. However, TAT-ZFN was difficult to purify in quantities sufficient for analysis in cell culture. Purified TAT-TALEN was able to penetrate cells and disrupt the gene encoding endogenous human chemokine (C-C motif) receptor 5 (CCR5, a co-receptor for HIV-1 entry into cells). Hypothermic treatment greatly enhanced the TAT-TALEN-mediated gene disruption efficiency. A 5% modification rate was observed in human induced pluripotent stem cells (hiPSCs) treated with TAT-TALEN as measured by the Surveyor assay. CONCLUSIONS: TAT-TALEN protein-mediated gene disruption was applicable in hiPSCs and represents a promising technique for gene knockout in stem cells. This new technique may advance the clinical application of TALEN technology.

Height loss, vertebral fractures, and the misclassification of osteoporosis.

BACKGROUND: The presence of a vertebral fracture identifies a patient who has clinical osteoporosis. However, approximately 2/3 to 3/4 of VFs are asymptomatic. Vertebral Fracture Assessment is a method derived from dual-energy X-ray absorptiometry (DXA) to assess vertebral fractures. The objectives of this study were 1) to determine the association between the degree of height loss in older men and women and the risk of a vertebral fracture, and 2) to determine if the knowledge of vertebral fractures will alter the classification of osteoporosis based on bone mineral density alone. METHODS: 231 men and women over the age of 65 underwent DXA scan of their spine and hip (including bone mineral density and Vertebral Fracture Assessment), measurement of their height, and a questionnaire. RESULTS: We found that height loss was significantly associated with a vertebral fracture (p=0.0160). The magnitude of the association translates to a 19% increase in odds for 1/2 in. and 177% for 3 in. Although 45% had osteoporosis by either bone mineral density or fracture criteria, 30% would have been misclassified if bone mineral density criteria were used alone. CONCLUSIONS: Height loss is an indicator for the presence of vertebral fractures. Bone mineral density criteria alone may misclassify older patients who have osteoporosis.