700,000 years of tropical Andean glaciation.

Our understanding of the climatic teleconnections that drove ice-age cycles has been limited by a paucity of well-dated tropical records of glaciation that span several glacial-interglacial intervals. Glacial deposits offer discrete snapshots of glacier extent but cannot provide the continuous records required for detailed interhemispheric comparisons. By contrast, lakes located within glaciated catchments can provide continuous archives of upstream glacial activity, but few such records extend beyond the last glacial cycle. Here a piston core from Lake Junín in the uppermost Amazon basin provides the first, to our knowledge, continuous, independently dated archive of tropical glaciation spanning 700,000 years. We find that tropical glaciers tracked changes in global ice volume and followed a clear approximately 100,000-year periodicity. An enhancement in the extent of tropical Andean glaciers relative to global ice volume occurred between 200,000 and 400,000 years ago, during sustained intervals of regionally elevated hydrologic balance that modified the regular approximately 23,000-year pacing of monsoon-driven precipitation. Millennial-scale variations in the extent of tropical Andean glaciers during the last glacial cycle were driven by variations in regional monsoon strength that were linked to temperature perturbations in Greenland ice cores1; these interhemispheric connections may have existed during previous glacial cycles.

Phase 1b/2a randomized study of heterologous ChAdOx1-HBV/MVA-HBV therapeutic vaccination (VTP-300) as monotherapy and combined with low-dose nivolumab in virally-suppressed patients with chronic hepatitis B.

BACKGROUND AND AIM: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T cell dysfunction during CHB. APPROACH AND RESULTS: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. The trial enrolled 55 patients with virally-suppressed CHB virus infection and HBsAg <4,000 IU/mL Group 1 received MVA-HBV intramuscularly (IM) on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0/MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections. VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in the VTP-300 group 2: 3 of 18 patients with starting HBsAg < 50 IU/ml had durable log10 declines > 0.7 log10 2 months post last-dose. Group 3 (N=18) had reductions in HBsAg of 0.76 log10 and 0.80 log10 3 (p<0.001) at 2 and 7 months post last dose. Two developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T cell responses were generated and there was a correlation between IFN-y ELISpot response and HBsAg decline in Group 2. CONCLUSIONS: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic to move forward alone or in combination therapies. IMPACT AND IMPLICATIONS: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic hepatitis B virus infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg in CHB patients, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor. The use of immunotherapeutics CLINTRIALS: NCT047789.

Isotope shifts in electron affinities and in binding energies of Pb and hyperfine structure of 207Pb.

The isotope shifts in electron affinities of Pb were measured by Walter et al. [Phys. Rev. A 106, L010801 (2022)] to be -0.002(4) meV for 207-208Pb and -0.003(4) meV for 206-208Pb by scanning the threshold of the photodetachment channel Pb-(S3/2◦4) - Pb (3P0), while Chen and Ning reported 0.015(25) and -0.050(22) meV for the isotope shifts on the binding energies measured relative to 3P2 using the SEVI method [J. Chem. Phys. 145, 084303 (2016)]. Here we revisited these isotope shifts by using our second-generation SEVI spectrometer and obtained -0.001(15) meV for 207-208Pb and -0.001(14) meV for 206-208Pb, respectively. In order to aid the experiment by theory, we performed the first ab initio theoretical calculations of isotope shifts in electron affinities and binding energies of Pb, as well as the hyperfine structure of 207Pb-, by using the MCDHF and RCI methods. The isotope shifts in electron affinities of 207-208Pb and 206-208Pb are -0.0023(8) and -0.0037(13) meV for the 3P0 channel, respectively, in good agreement with Walter et al.'s measurements. The isotope shifts in binding energies relative to 3P1,2, -0.0015(8) and -0.0026(13) meV for 207-208Pb and 206-208Pb, respectively, are compatible with the present measurements. The hyperfine constant for the ground state of 207Pb- obtained by the present calculations, A(S3/2◦4)=-1118 MHz, differs by a factor of 3 from the previous estimation by Bresteau et al. [J. Phys. B: At., Mol. Opt. Phys. 52, 065001 (2019)]. The reliability is supported by the good agreement between the theoretical and experimental hyperfine parameters of 209Bi.

A mathematical model on the propagation of tau pathology in neurodegenerative diseases.

A system of partial differential equations is developed to study the spreading of tau pathology in the brain for Alzheimer's and other neurodegenerative diseases. Two cases are considered with one assuming intracellular diffusion through synaptic activities or the nanotubes that connect the adjacent cells. The other, in addition to intracellular spreading, takes into account of the secretion of the tau species which are able to diffuse, move with the interstitial fluid flow and subsequently taken up by the surrounding cells providing an alternative pathway for disease spreading. Cross membrane transport of the tau species are considered enabling us to examine the role of extracellular clearance of tau protein on the disease status. Bifurcation analysis is carried out for the steady states of the spatially homogeneous system yielding the results that fast cross-membrane transport combined with effective extracellular clearance is key to maintain the brain's healthy status. Numerical simulations of the first case exhibit solutions of travelling wave form describing the gradual outward spreading of the pathology; whereas the second case shows faster spreading with the buildup of neurofibrillary tangles quickly elevated throughout. Our investigation thus indicates that the gradual progression of the intracellular spreading case is more consistent with the clinical observations of the development of Alzheimer's disease.

[Clinical analysis of 86 cases of acute fatty liver of pregnancy].

Objective: To investigate the clinical characteristics and maternal and fetal prognosis of pregnant women with acute fatty liver of pregnancy (AFLP). Methods: The clinical data of 86 AFLP pregnant women admitted to the Third Affiliated Hospital of Guangzhou Medical University from September 2017 to August 2022 were collected, and their general data, clinical characteristics, laboratory tests and maternal and fetal outcomes were retrospectively analyzed. Results: (1) General information: the age of the 86 pregnant women with AFLP was (30.8±5.4) years, and the body mass index was (21.0±2.5) kg/m2. There were 50 primiparas (58.1%, 50/86) and 36 multiparas (41.9%, 36/86). There were 64 singleton pregnancies (74.4%, 64/86) and 22 twin pregnancies (25.6%, 22/86). (2) Clinical characteristics: the main complaints of AFLP pregnant women were gastrointestinal symptoms, including epigastric pain (68.6%, 59/86), nausea (47.7%, 41/86), anorexia (46.5%, 40/86), vomiting (39.5%, 34/86). The main non-gastrointestinal symptoms were jaundice of skin and/or scleral (54.7%, 47/86), edema (38.4%, 33/86), fatigue (19.8%, 17/86), bleeding tendency (16.3%, 14/86), polydipsia or polyuria (14.0%, 12/86), skin itching (8.1%, 7/86), and 17.4% (15/86) AFLP pregnant women had no obvious symptoms. (3) Laboratory tests: the incidence of liver and kidney dysfunction and abnormal coagulation function in AFLP pregnant women was high, and the levels of blood ammonia, lactate dehydrogenase and lactic acid were increased, and the levels of hemoglobin, platelet and albumin decreased. However, only 24 cases (27.9%, 24/86) of AFLP pregnant women showed fatty liver by imageology examination. (4) Pregnancy outcomes: ① AFLP pregnant women had a high incidence of pregnancy complications, mainly including renal insufficiency (95.3%, 82/86), preterm birth (46.5%, 40/86), hypertensive disorders in pregnancy (30.2%, 26/86), gestational diabetes mellitus (36.0%, 31/86), fetal distress (24.4%, 21/86), pulmonary infection (23.3%, 20/86), disseminated intravascular coagulation (16.3%, 14/86), multiple organ dysfunction syndrome (16.3%, 14/86), hepatic encephalopathy (9.3%, 8/86), and intrauterine fetal death (2.3%, 2/86). ② Treatment and outcome of AFLP pregnant women: the intensive care unit transfer rate of AFLP pregnant women was 66.3% (57/86). 82 cases were improved and discharged after treatment, 2 cases were transferred to other hospitals for follow-up treatment, and 2 cases (2.3%, 2/86) died. ③ Neonatal outcomes: except for 2 cases of intrauterine death, a total of 106 neonates were delivered, including 39 cases (36.8%, 39/106) of neonatal asphyxia, 63 cases (59.4%, 63/106) of neonatal intensive care unit admission, and 3 cases (2.8%, 3/106) of neonatal death. Conclusions: AFLP is a severe obstetric complication, which is harmful to mother and fetus. In the process of clinical diagnosis and treatment, attention should be paid to the clinical manifestations and laboratory tests of pregnant women, early diagnosis and active treatment, so as to improve maternal and fetal outcomes.

Profiled polyethylene terephthalate filaments that incorporate collagen and calcium phosphate enhance ligamentisation and bone formation.

Polyethylene terephthalate (PET) artificial ligaments offer an unlimited source of ligaments without donor-site-related morbidity and with good mechanical properties for a rapid return to sporting activities. Developing PET artificial ligaments with excellent ligamentisation and ligament-bone healing is still a considerable challenge. This study aimed to investigate the effects of the profiled PET/collagen/calcium phosphate (PET/C/CaP) ligament upon cell growth, ligamentisation and ligament-bone healing in vitro and in vivo. Profiled PET/C/CaP filaments were made by melt-spinning process with 2 % CaP hybrid spinning and collagen coating. Rat mesenchymal stem cells (MSCs) were cultured on the profiled PET/C filaments for cytotoxicity, viability, scanning electron microscopy (SEM) and ligament-related gene expression analysis. MSCs' osteogenic capacity on the profiled PET/CaP filaments was identified by detecting osteogenic gene expression and alizarin red S staining. For in vivo verification, an animal study was performed to evaluate the effect of the profiled PET/C/CaP ligament in a rabbit knee medial collateral ligament reinforcement reconstruction model. The graft ligamentisation and bone formation were investigated by SEM, histology, microcomputed tomography and mechanical tests. The profiled PET/C filaments enhanced MSC proliferation and ligament-related gene expression. Furthermore, they enhanced osteogenic gene expression, alkaline phosphatase activity and mineralisation of MSCs. The in vivo study indicated that the profiled PET/C/CaP ligament enhanced ligamentous matrix remodelling and bone formation. Therefore, their use is an effective strategy for promoting MSCs' ligamentous and osteogenic potential in vitro and enhancing ligamentous matrix remodelling and bone formation in vivo.

Effects of daily almond consumption for six months on cognitive measures in healthy middle-aged to older adults: a randomized control trial.

BACKGROUND: Age-related cognitive decline is a major public health issue. Almonds are rich in nutrients that benefit cognitive function. OBJECTIVE: To investigate the impact of almonds on cognition in elderly adults. DESIGN: In a six-month, single-blinded, randomized-controlled trial, the effects of an almond intervention on cognition in healthy, middle-aged/older adults (50-75 years) was tested. Subjects were assigned to one of three groups: 1.5 oz/d almond (n = 19), 3 oz/d almond (n = 24), or 3.5 oz/d snack (control, matched for macronutrients in 3.0 oz almonds, (n = 17). Serum analyses for tocopherols, oxidative status and inflammation, and cognition were assessed at baseline (M0), three (M3), and six (M6) months. RESULTS: At M6, serum alpha-tocopherol concentrations increased by 8% from M0 (p < 0.05) in the 3 oz almond group but did not increase in the other groups. Serum markers of inflammation and oxidative stress were not significantly different throughout the study among the groups. There was no difference in change over time in cognitive tests among the groups. However, there was a significant improvement in visuospatial working memory (p = 0.023), visual memory and learning (p = 0.017), and spatial planning and working memory (p < 0.001) in subjects receiving 3 oz/d almonds at M6, while the snack group showed no improvement. CONCLUSIONS: Almonds did not significantly improve cognitive function in cognitively intact middle-aged/older adults over six months. However, a significant improvement at M6 in cognitive measures was observed with 3 oz/d almonds. While these results are encouraging, a study of longer duration in subjects at risk for age-related cognitive decline is warranted.Trial registration: ClinicalTrials.gov identifier: NCT03093896.

Situational risk factors for fall-related vertebral fractures in older men and women.

Situational factors might help explain why most vertebral fractures occur in older people without a previous osteoporosis diagnosis. After adjusting for predisposing risk factors, the activity before the fall, type of fall, and falling direction remained as strong determinants of fall-related vertebral fractures in older men and women. INTRODUCTION: A matched case-control study was conducted to investigate the effects of situational factors, in addition to predisposing factors, on clinical vertebral fractures in older men and women in Taiwan. METHODS: Cases were community-dwelling individuals aged ≥ 65 years who visited emergency departments (EDs) of two university-affiliated hospitals due to a fall and had a primary diagnosis of a vertebral fracture during a 1-year period in 2017. Five control patients per case, matched by the time of falling, gender, and age, who sought care in the same ED due to a fall resulting in a soft tissue injury were selected. A total of 64 men (age range: 65 ~ 99 years) and 194 women (age range: 65 ~ 100 years), diagnosed with a vertebral fracture, participated in the study. RESULTS: Multivariable logistic models were conducted separately for men and women. Results suggested that the following factors were significantly associated with an increased risk of vertebral fractures in men: a low educational level (adjusted odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.02 ~ 3.71), asthma (OR = 2.96; 95% CI, 1.35 ~ 6.92), depression (OR = 4.31; 95% CI, 1.03 ~ 17.5), toileting (OR = 2.30; 95% CI, 1.04 ~ 4.94), slipping (OR = 5.27; 95% CI, 1.80 ~ 15.4), stepping down (OR = 3.99; 95% CI, 1.40 ~ 11.4), sudden leg weakness (OR = 3.73; 95% CI, 1.13 ~ 12.4), and falling backwards (OR = 3.78; 95% CI, 1.83 ~ 7.80); and in women: a fracture history (OR = 2.00; 95% CI, 1.07 ~ 3.76), osteoporosis (OR = 1.94; 95% CI, 1.15 ~ 3.49), getting in/out of the bed/chair (OR = 1.90; 95% CI, 1.07 ~ 3.39), stepping down (OR = 2.10; 95% CI, 1.17 ~ 3.77), and falling backwards (OR = 4.00; 95% CI, 2.39 ~ 6.68) and sideways (OR = 2.61; 95% CI, 1.38 ~ 4.96). CONCLUSIONS: The combination of predisposing and situational risk factors may display a more comprehensive risk profile for the occurrence of VFs, and thus, interventions that add both types of risk factors may result in greater risk reduction of VFs, although those specifically targeted at situational risk factors during falls are limited and their effectiveness and efficiency remained to be explored.

Hybridization Dynamics in CeCoIn_{5} Revealed by Ultrafast Optical Spectroscopy.

We investigate the quasiparticle dynamics in the prototypical heavy fermion CeCoIn_{5} using ultrafast optical pump-probe spectroscopy. Our results indicate that this material system undergoes hybridization fluctuations before the establishment of heavy electron coherence, as the temperature decreases from ∼120 K (T^{†}) to ∼55 K (T^{*}). We reveal that the anomalous coherent phonon softening and damping reduction below T^{*} are directly associated with the emergence of collective hybridization. We also discover a distinct collective mode with an energy of ∼8 meV, which may be experimental evidence of the predicted unconventional density wave. Our findings provide important information for understanding the hybridization dynamics in heavy fermion systems.

Fruits, vegetables, and health: A comprehensive narrative, umbrella review of the science and recommendations for enhanced public policy to improve intake.

Fruit and vegetables (F&V) have been a cornerstone of healthy dietary recommendations; the 2015-2020 U.S. Dietary Guidelines for Americans recommend that F&V constitute one-half of the plate at each meal. F&V include a diverse collection of plant foods that vary in their energy, nutrient, and dietary bioactive contents. F&V have potential health-promoting effects beyond providing basic nutrition needs in humans, including their role in reducing inflammation and their potential preventive effects on various chronic disease states leading to decreases in years lost due to premature mortality and years lived with disability/morbidity. Current global intakes of F&V are well below recommendations. Given the importance of F&V for health, public policies that promote dietary interventions to help increase F&V intake are warranted. This externally commissioned expert comprehensive narrative, umbrella review summarizes up-to-date clinical and observational evidence on current intakes of F&V, discusses the available evidence on the potential health benefits of F&V, and offers implementation strategies to help ensure that public health messaging is reflective of current science. This review demonstrates that F&V provide benefits beyond helping to achieve basic nutrient requirements in humans. The scientific evidence for providing public health recommendations to increase F&V consumption for prevention of disease is strong. Current evidence suggests that F&V have the strongest effects in relation to prevention of CVDs, noting a nonlinear threshold effect of 800 g per day (i.e., about 5 servings a day). A growing body of clinical evidence (mostly small RCTs) demonstrates effects of specific F&V on certain chronic disease states; however, more research on the role of individual F&V for specific disease prevention strategies is still needed in many areas. Data from the systematic reviews and mostly observational studies cited in this report also support intake of certain types of F&V, particularly cruciferous vegetables, dark-green leafy vegetables, citrus fruits, and dark-colored berries, which have superior effects on biomarkers, surrogate endpoints, and outcomes of chronic disease.

Efficacy and safety of high-dose vs low-dose leucovorin in patients with colorectal cancer: systematic review and meta-analysis.

AIM: The clinical benefits of a combination of leucovorin and fluorouracil have been established in the treatment of colorectal cancer. Due to a leucovorin shortage in 2008, many institutions revised their protocols to reduce the dose of leucovorin. After the shortage was resolved, some hospitals still maintained their modified protocols. Thus, we conducted a systematic review to evaluate the efficacy and safety of low- vs high-dose leucovorin in the treatment of colorectal cancer. METHOD: The PubMed, Embase and Cochrane databases were searched for studies published before May 2019. The meta-analysis was performed to estimate the pooled effect sizes by using a random effect model. The primary outcomes were median survival time and tumour response rate. Secondary outcomes were haematological and nonhaematological toxicities. RESULTS: Eight randomized controlled trials and four retrospective studies were reviewed. The pooled median survival time was similar between the two dose levels (standard mean difference -0.06, 95% CI -0.19 to 0.08). The pooled tumour response rate was comparatively higher in the high-dose leucovorin regimen (OR 0.81; 95% CI 0.55-1.18). No statistically significant difference was found between the haematological and nonhaematological toxicities of the two groups. However, there were fewer diarrhoea events in the low-dose leucovorin regimen. CONCLUSION: Low-dose leucovorin regimens seemed feasible approaches for colorectal cancer treatment when the shortage happened, because both regimens manifested comparable outcomes in survival time and tumour response rate.

Ubiquinol (Reduced Coenzyme Q10) and Cellular Oxygen Consumption in Patients Undergoing Coronary Artery Bypass Grafting.

Ubiquinol is a fundamental component of cellular metabolism. Low ubiquinol levels have been associated with mortality. This was a substudy of a randomized trial in patients undergoing coronary artery bypass grafting. We drew blood before and after surgery. Ubiquinol or placebo was added to peripheral blood mononuclear cells for oxygen consumption (OCR) measurements. In vivo ubiquinol levels were lower postsurgery compared to presurgery (0.16 µmol/L [quartiles: 0.02-0.39], P = .01), although the difference disappeared when adjusting for hemoglobin levels (P = .30). There was no difference in presurgical basal (1.0 mL/min/mg [95% confidence interval [CI]: -0.9 to 2.2], P = .08) and maximal (0.5 mL/min/mg [95% CI: -4.3 to 7.3], P = .56) OCR in cells receiving ubiquinol or placebo. There was a difference in postsurgical basal (1.1 mL/min/mg [95% CI: 0.9-1.6], P < .001) and maximal (4.2 mL/min/mg [95% CI: 0.3-7.0], P = .01) OCR between the groups. We found no association between ubiquinol and OCR levels (all P > .05).

The effect of egg consumption on cardiometabolic health outcomes: an umbrella review.

OBJECTIVE: This umbrella review provides an overview of the consistency and gaps in the evidence base on eggs and cardiometabolic health. DESIGN: PubMed, Web of Science, Cochrane Library, the Nutrition Evidence Systematic Review and Agency for Healthcare Research and Quality databases were screened for evidence-based reviews in English that assessed human studies on egg consumption and cardiometabolic outcomes. RESULTS: Seven systematic reviews and fifteen meta-analyses were identified, with eighteen of these published since 2015. Overall, the systematic reviews were of low quality, while meta-analyses were of moderate- to high-quality. No association of increased egg intake and risks of heart disease or stroke in the general population were found in the meta-analyses. Increased risk of heart failure was noted in two meta-analyses that analysed the same three cohort studies. Five recent meta-analyses reported no increased risk of type 2 diabetes mellitus (T2DM) in the general population, although increased risk in US-based populations only has been reported. Older (<2013) meta-analyses reported increased risks of cardiovascular disease (CVD) or heart disease in T2DM populations, and no recent evidence-based reviews were identified. Finally, only one meta-analysis reported intervention studies specifically on eggs and biomarkers (i.e. lipids), and the results contradicted those from observation studies. CONCLUSIONS: Recent evidence-based reviews conclude that increased egg consumption is not associated with CVD risk in the general population. More research is needed on the positive associations between egg consumption and heart failure and T2DM risk, as well as CVD risk in diabetics, before firm conclusions can be made.

Colistin and tylosin enhances disaccharidase activities, and improves morphology and permeability of the intestine of broilers.

1. The present study focused on the potential effects of antibiotics on intestinal digestion and integrity in broilers in terms of disaccharidase activity, electrophysiological properties and morphology. 2. One-day-old Arbour Acres birds were randomly allocated to one of four treatment groups for 42 days; control, colistin (20 mg/kg), tylosin (55 mg/kg) or chlortetracycline (CTC, 55 mg/kg) groups. Colistin and tylosin supplementation, but not CTC supplementation, caused an increase in body weight gain. 3. Colistin and tylosin elevated the activities of maltase and sucrase in the mucosa of the jejunum on d 42. Age caused a gradual decrease in the short-circuit current (Isc) and conductance (Gt) of the ileum, as a measure of permeability. The Isc and Gt of the ileum were higher in the colistin-supplemented broilers than in the control birds on d 42. Tylosin- and CTC-supplemented birds displayed Isc and Gt values similar to those of the control birds. 4. Colistin supplementation increased the villus area in the jejunum and thinned the muscularis mucosae in the ileum compared with the control group. Tylosin supplementation decreased the thickness of the muscularis mucosae and the depth of crypt in the jejunum. CTC thickened the muscularis mucosae in the jejunum and ileum. 5. Colistin and tylosin exhibited a beneficial effect on intestinal digestion and integrity by enhancing disaccharidase activities and improving gut morphology and permeability.

[The relationship between adherens junction and tight junction and clinical symptoms in patients with diarrhea predominant irritable bowel syndrome].

Objective: To investigate the association between adherens junction proteins E-cadherin and ß-catenin and tight junction protein claudin-2 and clinical symptoms in patients with diarrhea predominant irritable bowel syndrome (IBS-D). Methods: Cecal biopsy tissues were collected from IBS-D patients (n=26) according to Rome Ⅲ criterion and healthy controls (n=26). The duration of symptoms, abdominal pain score and mean weekly bowel movements were recorded. Colorectal dilatation combined with restraint stress were applied to establish visceral hypersensitivity rat model. Abdominal contraction reflex (AWR) was applied to assess the visceral sensitivity in rats. The stool frequency within 1 hour was recorded after establishing the rat model. The expression of E-cadherin、ß-catenin and claudin-2 were assessed by Western blot and immunofluorescence microscopy. Intercellular ultrastructure was observed by transmission electron microscopy. Results: Compared with the healthy controls, the protein expression of E-cadherin and ß-catenin in cecal epithelium in IBS-D patients were significantly lower (P=0.015 and P=0.005, respectively), while claudin-2 was significantly higher (P=0.000). Reduced E-cadherin and ß-catenin expression was associated high abdominal pain score (r=-0.463, P=0.017 and r=-0.407, P=0.039). The lower expression of ß-catenin was associated with longer duration of symptoms (r=-0.458, P=0.019). The protein expression of E-cadherin and ß-catenin in the cecal epithelium of the visceral hypersensitivity rats were significantly lower (P=0.004 and P=0.003, respectively), while claudin-2 was significantly higher (P=0.008). Reduced E-cadherin and ß-catenin expression was associated high visceral sensitivity in IBS-D rats (r=-0.639, P=0.047 and r=-0.888, P=0.001). Conclusions: Intercellular ultrastructure alterations well as cecal ß-catenin and E-cadherin protein expression decrease and are associated with high abdominal pain score in IBS-D patients and hypersensitivity rats. ß-catenin is further associated with prolonged duration of symptoms in IBS-D patients. The expression of E-cadherin and ß-catenin may play a vital role in visceral sensitivity and intestinal barrier dysfunction in IBS-D.

[A new strategy for non-invasive diagnosis of liver diseases: DSA-FACE technology based-glycomics method].

Chronic liver disease has gradually become a serious health problem worldwide. Liver biopsy is the current gold standard to assess liver lesions; however, it is an invasive procedure that may cause severe complications. Therefore, there is an urgent need for an economical and rapid non-invasive detection method that can be used in clinic for diagnosis. In the past decade, protein glycosylation has become a research hotspot, and the concept of changes in serum proteoglycans structure has gradually been accepted by many researchers as an indication of liver injury. At the same time, N-linked glycans via DNA sequencing equipment-Fluorophore Assisted Carbohydrate Electrophoresis (DSA-FACE) has also brought high sensitivity and specificity diagnostic models (GlycoHepatoTest) for various chronic liver diseases, which is a new strategy for non-invasive diagnosis of liver diseases.

[Application of serum N -glycan profiling diagnostic model in evaluation of liver fibrosis in patients with hepatitis C].

Objective: To study the changes of serum N-glycan abundance in patients with liver fibrosis at different stages of hepatitis C, and to establish and evaluate the diagnostic model for clinical application value. Methods: Data of 169 hepatitis C virus-infected cases with liver fibrosis were enrolled. Nine kinds of serum N-glycans were detected and analyzed using DNA sequencer-assisted fluorophore-assisted capillary electrophoresis technology. A binary logistics regression method was used to establish a diagnostic model based on the changes in the relative content of N-glycans in each stage of liver fibrosis. Receiver operating characteristic curve was used to evaluate and compare the diagnostic efficacy with other liver fibrosis diagnostic models. Results: N-glycan diagnostic model (B and C) had highest AUROC= 0.776, 0.827 for distinguishing fibrosis S1~S2 to S3~S4 and S1~S3 to S4 than GlycoFibroTest (AUROC = 0.760, 0.807), GlycoCirrhoTest (AUROC = 0.722, 0.787), aspartate aminotransferase to platelet ratio index (AUROC = 0.755, 0.751), FIB-4 index (AUROC = 0.730, 0.774), and S-index (AUROC = 0.707, 0.744). However, the diagnostic efficacy of model A (AUROC = 0.752) for distinguishing fibrosis S1 with S2~S4 had lower diagnostic potency than that of the aspartate aminotransferase to platelet ratio index (AUROC = 0.807). Diagnostic efficiency was improved when the N-glycan profiling and the aspartate aminotransferase to platelet ratio index were combined to diagnose liver fibrosis in each stage, and the area under the receiver operating characteristic curve was 0.839, 0.825, and 0.837, respectively. Conclusion: The serum N-glycan profiling diagnostic model has potential clinical application value in the diagnosis of liver fibrosis in patients with hepatitis C.

Modelling the outbreak of infectious disease following mutation from a non-transmissible strain.

In-host mutation of a cross-species infectious disease to a form that is transmissible between humans has resulted with devastating global pandemics in the past. We use simple mathematical models to describe this process with the aim to better understand the emergence of an epidemic resulting from such a mutation and the extent of measures that are needed to control it. The feared outbreak of a human-human transmissible form of avian influenza leading to a global epidemic is the paradigm for this study. We extend the SIR approach to derive a deterministic and a stochastic formulation to describe the evolution of two classes of susceptible and infected states and a removed state, leading to a system of ordinary differential equations and a stochastic equivalent based on a Markov process. For the deterministic model, the contrasting timescale of the mutation process and disease infectiousness is exploited in two limits using asymptotic analysis in order to determine, in terms of the model parameters, necessary conditions for an epidemic to take place and timescales for the onset of the epidemic, the size and duration of the epidemic and the maximum level of the infected individuals at one time. Furthermore, the basic reproduction number R0 is determined from asymptotic analysis of a distinguished limit. Comparisons between the deterministic and stochastic model demonstrate that stochasticity has little effect on most aspects of an epidemic, but does have significant impact on its onset particularly for smaller populations and lower mutation rates for representatively large populations. The deterministic model is extended to investigate a range of quarantine and vaccination programmes, whereby in the two asymptotic limits analysed, quantitative estimates on the outcomes and effectiveness of these control measures are established.

Largest GWAS of PTSD (N=20 070) yields genetic overlap with schizophrenia and sex differences in heritability.

The Psychiatric Genomics Consortium-Posttraumatic Stress Disorder group (PGC-PTSD) combined genome-wide case-control molecular genetic data across 11 multiethnic studies to quantify PTSD heritability, to examine potential shared genetic risk with schizophrenia, bipolar disorder, and major depressive disorder and to identify risk loci for PTSD. Examining 20 730 individuals, we report a molecular genetics-based heritability estimate (h2SNP) for European-American females of 29% that is similar to h2SNP for schizophrenia and is substantially higher than h2SNP in European-American males (estimate not distinguishable from zero). We found strong evidence of overlapping genetic risk between PTSD and schizophrenia along with more modest evidence of overlap with bipolar and major depressive disorder. No single-nucleotide polymorphisms (SNPs) exceeded genome-wide significance in the transethnic (overall) meta-analysis and we do not replicate previously reported associations. Still, SNP-level summary statistics made available here afford the best-available molecular genetic index of PTSD-for both European- and African-American individuals-and can be used in polygenic risk prediction and genetic correlation studies of diverse phenotypes. Publication of summary statistics for ∼10 000 African Americans contributes to the broader goal of increased ancestral diversity in genomic data resources. In sum, the results demonstrate genetic influences on the development of PTSD, identify shared genetic risk between PTSD and other psychiatric disorders and highlight the importance of multiethnic/racial samples. As has been the case with schizophrenia and other complex genetic disorders, larger sample sizes are needed to identify specific risk loci.

Chronic consumption of a low calorie, high polyphenol cranberry beverage attenuates inflammation and improves glucoregulation and HDL cholesterol in healthy overweight humans: a randomized controlled trial.

PURPOSE: We studied the health benefits of low calorie cranberry beverage consumption on glucoregulation, oxidative damage, inflammation, and lipid metabolism in overweight but otherwise healthy humans. METHODS: 78 overweight or obese men and women (30-70 years; BMI 27-35 kg/m2) with abdominal adiposity (waist: hip > 0.8 for women and > 0.9 for men; waist: height ≥ 0.5) consumed 450 mL placebo or low calorie, high polyphenol cranberry extract beverage (CEB) daily for 8 week in a randomized, double-blind, placebo-controlled, parallel design trial. Blood and urine samples were collected after overnight fast at baseline and after 8 weeks of daily beverage consumption. Blood and urine samples were also collected during 3 oral glucose tolerance test (OGTT) challenges: (1) pre-intervention without the test beverages, (2) following a single dose of placebo or CEB at baseline (week 0), and (3) following a single dose of placebo or CEB at 8 week. RESULTS: Compared to placebo, a single CEB dose at baseline lowered endothelin-1 and elevated nitric oxide and the reduced:oxidized glutathione ratio (P < 0.05). Interferon-γ was elevated (P < 0.05) after a single CEB dose at baseline; however, after 8 week of CEB intervention, fasting C-reactive protein was lower (P < 0.05). CEB consumption for 8 week also reduced serum insulin and increased HDL cholesterol compared to placebo (P < 0.05). CONCLUSIONS: An acute dose of low calorie, high polyphenol cranberry beverage improved antioxidant status, while 8 week daily consumption reduced cardiovascular disease risk factors by improving glucoregulation, downregulating inflammatory biomarkers, and increasing HDL cholesterol.