Fast Energy Storage in Two-Dimensional MoO2 Enabled by Uniform Oriented Tunnels.
While pseudocapacitive electrodes have potential to store more energy than electrical double-layer capacitive electrodes, their rate capability is often limited by the sluggish kinetics of the Faradaic reactions or poor electronic and ionic conductivity. Unlike most transition-metal oxides, MoO2 is a very promising material for fast energy storage, attributed to its unusually high electronic and ionic conductivity; the one-dimensional tunnel is ideally suited for fast ionic transport. Here we report our findings in preparation and characterization of ultrathin MoO2 sheets with oriented tunnels as a pseudocapacitive electrode for fast charge storage/release. A composite electrode consisting of MoO2 and 5 wt % GO demonstrates a capacity of 1097 C g-1 at 2 mV s-1 and 390 C g-1 at 1000 mV s-1 while maintaining ∼80% of the initial capacity after 10,000 cycles at 50 mV s-1, due to minimal change in structural features of the MoO2 during charge/discharge, except a small volume change (∼14%), as revealed from operando Raman spectroscopy, X-ray analyses, and density functional theory calculations. Further, the volume change during cycling is highly reversible, implying high structural stability and long cycling life.


In vitro and in vivo effects of three different Mitragyna speciosa korth leaf extracts on phase II drug metabolizing enzymes--glutathione transferases (GSTs).
In the present study, we investigate the effects of three different Mitragyna speciosa extracts, namely methanolic, aqueous and total alkaloid extracts, on glutathione transferase-specific activity in male Sprague Dawley rat liver cytosol in vitro and in vivo. In the in vitro study, the effect of Mitragyna speciosa extracts (0.01 to 750 microg/mL) against the specific activity of glutathione transferases was examined in rat liver cytosolic fraction from untreated rats. Our data show concentration dependent inhibition of cytosolic GSTs when Mitragyna speciosa extract was added into the reaction mixture. At the highest concentration used, the methanolic extract showed the highest GSTs specific activity inhibition (61%), followed by aqueous (50%) and total alkaloid extract (43%), respectively. In in vivo study, three different dosages; 50, 100 and 200 mg/kg for methanolic and aqueous extracts and 5, 10 and 20 mg/kg for total alkaloid extract were given orally for 14 days. An increase in GST specific activity was generally observed. However, only Mitragyna speciosa aqueous extract with a dosage of 100 mg/kg showed significant results: 129% compared to control.


[Malignant fibrous histiocytoma of the esophagus].
The patient aged 60 underwent extirpation of the thoracic oesophagus followed by esophagogastroplasty and splenectomy. There was a polyp-like neoplasm 12 cm long and 3 cm in diameter on a crus originating from the esophageal wall and diagnosed histologically as a malignant fibrous histiocytoma infiltrating muscular coat at the site of the crus. The patient died of suppurative mediastinitis 8 days later.


Evaluating the Effect of CPP-ACP as a Final Irrigant in Improving the Micro-Hardness of Erosive Root Dentin and its Influence on the Bond Strength of Self Etch Resin Sealer - An In-vitro Study.
Smear layer removal from the root canal wall involves the use of 17% EDTA and 5.25% sodium hypochlorite, which thereby improves the adhesion of obturating materials to root dentin. But these chemical irrigants have shown to decrease micro hardness, increase roughness, cause erosion and reduce the root dentin fracture toughness. To combat these adverse effects, studies can be focussed on the remineralisation of the erosive root dentin and this novel idea has been utilized in the present study. To evaluate the micro hardness of erosive root dentin when Casein Phosphopeptide-Amorphous Calcium Phosphate (CPP-ACP) was used as a final irrigant and its influence on resin sealer bonding tested by push-out bond strength method. Sixty extracted maxillary incisors were divided into three groups based on the final irrigation protocol. Group 1-normal saline, Group 2-17% EDTA (Ethylene Diamine Tetraacetic Acid) + 5.25% NaOCl (Sodium Hypochlorite), Group 3 - 17% EDTA + 5.25% NaOCl + CPP-ACP; each group was divided into two subgroups. Half the specimens of each group were evaluated for Vicker's micro hardness test after the treatment. In continuation with the above methodology the remaining specimens were tested for push-out bond strength after obturation of the specimens with self etch adhesive resin sealer and conventional 6% gutta percha cones. Micro hardness was statistically analysed using Kruskal Wallis test and push-out bond strength was evaluated using Mann Whitney test and paired t-test. CPP-ACP treated group showed increased micro hardness (p<0.05). There was no statistically significant difference between the push-out bond strength values between group EDTA + NaOCl group and EDTA + NaOCl + CPP-ACP group. Within the limitations of this study it can be concluded that, CPP-ACP improved the micro hardness of erosive root dentin and is not affecting its bond strength. Therefore, CPP-ACP may be used before bonding procedures for promoting remineralization of root dentin.


Stress symptoms among adolescents: the role of subjective psychosocial conditions, lifestyle, and self-esteem.
Stress-related problems are increasing among Swedish adolescents, especially among females. The aims of this study were to survey the incidence of stress symptoms among 16-year-olds, to investigate the related gender differences, and to understand the factors that may contribute to stress symptoms. The study is questionnaire based, and the sample included 304 first-year high school students from two comparable schools. More than 30% of the high school students reported serious stress symptoms. Almost every second girl and every fifth boy reported that they felt stressed to a high degree. 8.2% were found to have severe stress symptoms, which would be considered a sign of chronic stress in adults. Besides the perception of high demands, low levels of global self-esteem, sleep disturbances, and poor social support played a crucial role in the prediction of stress symptoms. The findings highlight the need to develop and implement adequate stress prevention measures for adolescents.


[Morphologic and applied aspects of mitotic pathology].
The author presents a classification and descriptions of various forms of pathology of mitosis. Changes in the mitotic regimen following administration of some drugs and under the effect of extreme factors are considered. Data on changes in the number and character of pathological mitoses in viral infection and radiation damage are discussed. Particular attention is given to the analysis of shifts in the mitotic regimen in various benign and malignant hyperplasia. It is shown that malignization (precancer and cancer of the larynx, endometrium, cervix uteri and stomach) is characterized by a rise of the mitotic activity, detection of division in metaphase and by a drastic increase in the number of pathological mitoses. These indices are used in the differential diagnosis of neoplastic processes and for early detection of possible malignization pf precancer hyperplasia.


Genomic expression analysis of rat chromosome 4 for skeletal traits at femoral neck.
Hip fracture is the most devastating osteoporotic fracture type with significant morbidity and mortality. Several studies in humans and animal models identified chromosomal regions linked to hip size and bone mass. Previously, we identified that the region of 4q21-q41 on rat chromosome (Chr) 4 harbors multiple femoral neck quantitative trait loci (QTLs) in inbred Fischer 344 (F344) and Lewis (LEW) rats. The purpose of this study is to identify the candidate genes for femoral neck structure and density by correlating gene expression in the proximal femur with the femoral neck phenotypes linked to the QTLs on Chr 4. RNA was extracted from proximal femora of 4-wk-old rats from F344 and LEW strains, and two other strains, Copenhagen 2331 and Dark Agouti, were used as a negative control. Microarray analysis was performed using Affymetrix Rat Genome 230 2.0 arrays. A total of 99 genes in the 4q21-q41 region were differentially expressed (P < 0.05) among all strains of rats with a false discovery rate <10%. These 99 genes were then ranked based on the strength of correlation between femoral neck phenotypes measured in F2 animals, homozygous for a particular strain's allele at the Chr 4 QTL and the expression level of the gene in that strain. A total of 18 candidate genes were strongly correlated (r(2) > 0.50) with femoral neck width and prioritized for further analysis. Quantitative PCR analysis confirmed 14 of 18 of the candidate genes. Ingenuity pathway analysis revealed several direct or indirect relationships among the candidate genes related to angiogenesis (VEGF), bone growth (FGF2), bone formation (IGF2 and IGF2BP3), and resorption (TNF). This study provides a shortened list of genetic determinants of skeletal traits at the hip and may lead to novel approaches for prevention and treatment of hip fracture.


Cigarette smoking, gastric acid secretion, and serum pepsinogen I concentrations in duodenal ulcer patients.
Cigarette smoking has been linked with duodenal ulcer disease although the mechanism of this association is unclear. This study assessed basal gastric secretory response to acute smoking of smokers with an active duodenal ulcer; in addition the possible effects of chronic smoking on gastric secretory capacity, as expressed by pentagastrin stimulated gastric acid secretion and fasting serum pepsinogen I (PG I) concentrations, were investigated in patients with active duodenal ulcer, or non-ulcer dyspepsia. In 10 smokers with duodenal ulcer smoking four cigarettes during 40 minutes did not influence basal gastric secretion of acid and pepsin, or serum PG I and gastrin concentrations. In 136 patients with duodenal ulcer and 90 controls with non-ulcer dyspepsia, pentagastrin stimulated acid secretion and fasting serum PG I concentrations were significantly higher among habitual heavy smokers than among non-smokers. These findings suggest that in heavy smokers with duodenal ulcer acid- and pepsin-secreting cell function is not affected by acute cigarette smoking. By contrast, chronic cigarette smoking seems to be associated either with an increase of parietal- and chief-cell mass, or with an enhancement of their secretory capacity.


The efficacy of some probiotics and prebiotics on the prevalence of E. coli and the immune response of chickens.
The present study aimed to investigate the efficacy of probiotics and prebiotics in controlling Escherichia coli (E. coli) spp. isolated from chicken. A total of 230 birds representing 19 different commercial breeds were taken from various points. Birds were monitored for postmortem and clinical investigation. Aseptically collected liver samples, lungs, kidneys, hearts, and yolk sacs were then subjected to bacterial isolation and identification. E. coli were observed in 9 pooled samples from 120 examined with an incidence of 7.5%. Nine farms were E. coli-positive, with an incidence of farm infection of 47.3%. The 9 suspected isolates of E. coli were profiled by morphological and microbiological identification of the colony, motility, and gram reaction. The serogroup analysis showed 9 different E. coli for which 3 other groups were identified: 2 E. coli O78, 3 E. coli O111, and 4 untyped groups. Nine isolates of E. coli were subjected to PCR. Molecular detection of 9 strains was conducted to find the virulence genes of E. coli strains (8 STX1, 4 STX2, and 9 EAE). Probiotics and prebiotics significantly increased the total erythrocytic and leukocytic counts throughout the experiment. The phagocytic percentage's main values at 14 d were 47 and 30%, respectively. An increase in the humoral immunity against Newcastle disease (ND) was noticed after ND vaccination. The geometric mean (HI) was 5.9 and 4.2 for probiotic and prebiotic, respectively. It could be concluded that probiotics and prebiotics could stimulate a nonspecific immune response against experimental infection with a virulent strain of E. coli spp.


Endogenous diterpenes derived from ent-kaurene, a common gibberellin precursor, regulate protonema differentiation of the moss Physcomitrella patens.
Gibberellins (GAs) are a group of diterpene-type plant hormones biosynthesized from ent-kaurene via ent-kaurenoic acid. GAs are ubiquitously present in seed plants. The GA signal is perceived and transduced by the GID1 GA receptor/DELLA repressor pathway. The lycopod Selaginella moellendorffii biosynthesizes GA and has functional GID1-DELLA signaling components. In contrast, no GAs or functionally orthologous GID1-DELLA components have been found in the moss Physcomitrella patens. However, P. patens produces ent-kaurene, a common precursor for GAs, and possesses a functional ent-kaurene synthase, PpCPS/KS. To assess the biological role of ent-kaurene in P. patens, we generated a PpCPS/KS disruption mutant that does not accumulate ent-kaurene. Phenotypic analysis demonstrates that the mutant has a defect in the protonemal differentiation of the chloronemata to caulonemata. Gas chromatography-mass spectrometry analysis shows that P. patens produces ent-kaurenoic acid, an ent-kaurene metabolite in the GA biosynthesis pathway. The phenotypic defect of the disruptant was recovered by the application of ent-kaurene or ent-kaurenoic acid, suggesting that ent-kaurenoic acid, or a downstream metabolite, is involved in protonemal differentiation. Treatment with uniconazole, an inhibitor of ent-kaurene oxidase in GA biosynthesis, mimics the protonemal phenotypes of the PpCPS/KS mutant, which were also restored by ent-kaurenoic acid treatment. Interestingly, the GA(9) methyl ester, a fern antheridiogen, rescued the protonemal defect of the disruption mutant, while GA(3) and GA(4), both of which are active GAs in angiosperms, did not. Our results suggest that the moss P. patens utilizes a diterpene metabolite from ent-kaurene as an endogenous developmental regulator and provide insights into the evolution of GA functions in land plants.


Comparison of Satisfaction With Comorbid Depression Care Models Among Low-Income Patients With Diabetes.
Patient satisfaction is a patient-reported outcome with the potential to assess and improve the quality of newer care-management models such as remote patient monitoring using telecommunication technology. To evaluate differences in patient satisfaction among 3 care management groups in a comparative effectiveness trial. This study analyzed a comparative effectiveness trial that tested automated remote assessment technology-facilitated comorbid depression care-management (TC, n = 254) in comparison to team-supported depression care (SC, n = 228) and usual primary care (UC, n = 218) among low-income patients with type 2 diabetes. Relationships between patient satisfaction and care group were evaluated at each 6-month phase up to 18 months using linear regression models that controlled for depression status, diabetes symptoms, patient characteristics, and study group differences. While receiving care management, SC and TC patients were significantly more satisfied with depression care than UC patients. No consistently significant associations between patient satisfaction and patient characteristics or disease symptoms were found. Patient satisfaction was found to be influenced by elements of care-management, not by patient characteristics or disease symptoms. Results suggest greater patient satisfaction with depression care in a care-management model than UC, whether through clinician team support or automated remote monitoring technology.


Synthesis and biological characterization of novel charge-deficient spermine analogues.
Biogenic polyamines, spermidine and spermine, are positively charged at physiological pH. They are present in all cells and essential for their growth and viability. Here we synthesized three novel derivatives of the isosteric charge-deficient spermine analogue 1,12-diamino-3,6,9-triazadodecane (SpmTrien, 5a) that are N(1)-Ac-SpmTrien (5c), N(12)-Ac-SpmTrien (5b), and N(1),N(12)-diethyl-1,12-diamino-3,6,9-triazadodecane (N(1),N(12)-Et(2)-SpmTrien, 5d). 5a and 5d readily accumulated in DU145 cells at the same concentration range as natural polyamines and moderately competed for the uptake with putrescine (1) but not with spermine (4a) or spermidine (2). 5a efficiently down-regulated ornithine decarboxylase and decreased polyamine levels, while 5d proved to be inefficient, compared with N(1),N(11)-diethylnorspermine (6). None of the tested analogues were substrates for human recombinant spermine oxidase, but those having free aminoterminus, including 1,8-diamino-3,6-diazaoctane (Trien, 3a), were acetylated by mouse recombinant spermidine/spermine N(1)-acetyltransferase. 5a was acetylated to 5c and 5b, and the latter was further metabolized by acetylpolyamine oxidase to 3a, a drug used to treat Wilson's disease. Thus, 5a is a bioactive precursor of 3a with enhanced bioavailability.


A genome-wide association study of the frailty index highlights brain pathways in ageing.
Frailty is a common geriatric syndrome and strongly associated with disability, mortality and hospitalization. Frailty is commonly measured using the frailty index (FI), based on the accumulation of a number of health deficits during the life course. The mechanisms underlying FI are multifactorial and not well understood, but a genetic basis has been suggested with heritability estimates between 30 and 45%. Understanding the genetic determinants and biological mechanisms underpinning FI may help to delay or even prevent frailty. We performed a genome-wide association study (GWAS) meta-analysis of a frailty index in European descent UK Biobank participants (n = 164,610, 60-70 years) and Swedish TwinGene participants (n = 10,616, 41-87 years). FI calculation was based on 49 or 44 self-reported items on symptoms, disabilities and diagnosed diseases for UK Biobank and TwinGene, respectively. 14 loci were associated with the FI (p < 5*10-8 ). Many FI-associated loci have established associations with traits such as body mass index, cardiovascular disease, smoking, HLA proteins, depression and neuroticism; however, one appears to be novel. The estimated single nucleotide polymorphism (SNP) heritability of the FI was 11% (0.11, SE 0.005). In enrichment analysis, genes expressed in the frontal cortex and hippocampus were significantly downregulated (adjusted p < 0.05). We also used Mendelian randomization to identify modifiable traits and exposures that may affect frailty risk, with a higher educational attainment genetic risk score being associated with a lower degree of frailty. Risk of frailty is influenced by many genetic factors, including well-known disease risk factors and mental health, with particular emphasis on pathways in the brain.


Seroprevalence and risk factors of chikungunya virus infection in Mayotte, Indian Ocean, 2005-2006: a population-based survey.
Since 2006, Chikungunya virus (CHIKV) has re-emerged as an important pathogen of global concern. However, individual and household factors associated with the acquisition and the magnitude of clinically silent CHIKV infections remain poorly understood. In this present study, we aimed to investigate the seroprevalence, estimate the proportion of symptomatic illness and identify the risk factors for CHIKV infection in the primo-exposed population of Mayotte. METHODS/ PRINCIPAL FINDINGS: We conducted a household-based cross sectional serosurvey in Mayotte in November and December 2006 using complex multistage cluster sampling. To produce the results representative of the island population aged 2 years or older, sample data were adjusted with sample weights. Explanatory and multiple logistic regression analyses were performed to investigate associations between CHIKV infection seropositivity (presence of IgM and/or IgG to CHIKV by enzyme-linked immunoabsorbent assay) and risk factors. A total of 1154 individuals were analyzed. The overall seroprevalence of CHIKV infection was 37.2% (95% CI = 33.9-40.5), 318 (72.3%) of the seropositive participants reported symptoms consistent with a CHIKV infection during the epidemic period. Risk factors for CHIKV seropositivity among adults (aged 15 years and older) were male gender, low socioeconomic index, schooling < or = 6 years and living in makeshift housing. Our findings indicate that roughly one out of four CHIKV infections is asymptomatic. Conditions associated with poverty may be considered as critical in CHIKV acquisition. Thus, these conditions should be taken into account in the development of future prevention strategies of CHIKV disease.


The zebrafish flotte lotte mutant reveals that the local retinal environment promotes the differentiation of proliferating precursors emerging from their stem cell niche.
It is currently unclear how intrinsic and extrinsic mechanisms cooperate to control the progression from self-renewing to neurogenic divisions in retinal precursor cells. Here, we use the zebrafish flotte lotte (flo) mutant, which carries a mutation in the elys (ahctf1) gene, to study the relationship between cell cycle progression and neuronal differentiation by investigating how proliferating progenitor cells transition towards differentiation in a retinal stem cell niche termed the ciliary marginal zone (CMZ). In zebrafish embryos without Elys, CMZ cells retain the capacity to proliferate but lose the ability to enter their final neurogenic divisions to differentiate as neurons. However, mosaic retinae composed of wild-type and flo cells show that despite inherent cell cycle defects, flo mutant cells progress from proliferation to differentiation when in the vicinity of wild-type retinal neurons. We propose that the differentiated retinal environment limits the proliferation of precursors emerging from the CMZ in a manner that explains the spatial organisation of cells in the CMZ and ensures that proliferative retinal progenitors are driven towards differentiation.


Improving extracellular vesicles visualization: From static to motion.
In the last decade, extracellular vesicles (EVs) have become a hot topic. The findings on EVs content and effects have made them a major field of interest in cancer research. EVs, are able to be internalized through integrins expressed in parental cells, in a tissue specific manner, as a key step of cancer progression and pre-metastatic niche formation. However, this specificity might lead to new opportunities in cancer treatment by using EVs as devices for drug delivery. For future applications of EVs in cancer, improved protocols and methods for EVs isolation and visualization are required. Our group has put efforts on developing a protocol able to track the EVs for in vivo internalization analysis. We showed, for the first time, the videos of labeled EVs uptake by living lung cancer cells.


Fucoidan-induced osteogenic differentiation promotes angiogenesis by inducing vascular endothelial growth factor secretion and accelerates bone repair.
Osteogenesis and angiogenesis, including cell-cell communication between blood vessel cells and bone cells, are essential for bone repair. Fucoidan is a chemical compound that has a variety of biological activities. It stimulates osteoblast differentiation in human mesenchymal stem cells (MSCs), which in turn induces angiogenesis. However, the mechanism by which this communication between osteoblasts and endothelial cells is mediated remains unclear. Thus, the aim of this study was to clarify the relationship between fucoidan-induced osteoblastic differentiation in MSCs and angiogenesis in endothelial cells. First, the effect was confirmed of fucoidan on osteoblast differentiation in MSCs and obtained conditioned media from these cells (Fucoidan-MSC-CM). Next, the angiogenic activity of Fucoidan-MSC-CM was investigated and it was found that it stimulated angiogenesis, demonstrated by proliferation, tube formation, migration and sprout capillary formation in human umbilical vein endothelial cells. Messenger ribonucleic acid expression and protein secretion of vascular endothelial growth factor (VEGF) were dramatically increased during fucoidan-induced osteoblast differentiation and that its angiogenic activities were reduced by a VEGF/VEGF receptor-specific binding inhibitor. Furthermore, Fucoidan-MSC-CM increased the phosphorylation of mitogen-activated protein kinase and PI3K/AKT/eNOS signalling pathway, and that its angiogenic effects were markedly suppressed by SB203580 and AKT 1/2 inhibitor. Finally, an in vivo study was conducted and it was found that fucoidan accelerated new blood vessel formation and partially promoted bone formation in a rabbit model of a calvarial bone defect. This is the first study to investigate the angiogenic effect of fucoidan-induced osteoblastic differentiation through VEGF secretion, suggesting the therapeutic potential of fucoidan for enhancing bone repair.


The use of surgery in a real-world clinic to diagnose and treat pulmonary cryptococcosis in immunocompetent patients.
We evaluated the role played by surgery in the diagnosis and treatment of pulmonary cryptococcosis (PC) in immunocompetent subjects. We retrospectively studied 53 immunocompetent patients who were pathologically diagnosed with PC between January 2000 and December 2016 in a tertiary referral center. We compared the radiological presentations of, and diagnostic modalities used to evaluate, patients diagnosed both surgically and non-surgically. We also compared the treatment outcomes of patients who underwent surgical resection alone and those who received additional antifungals following surgical resection. Of the 53 patients, 30 (57%) were diagnosed via non-surgical modalities including percutaneous needle biopsy (PCNB) (n=29) and transbronchial lung biopsy (TBLB) (n=1); and 23 (43%) were diagnosed by surgical modalities including video-assisted thoracoscopic wedge resection (n=22) and lobectomy (n=1). An initial clinical suspicion of a lung malignancy was associated with the use of surgical diagnostic approaches (P<0.001). Whereas undetermined locations were associated with the use of surgical diagnostic approaches, radiological findings such as clustered nodular patterns (P<0.001), cavities (P=0.005), air bronchograms (P<0.001), and peripheral lesions (P<0.001) were associated with the use of non-surgical diagnostic approaches. Of the 30 non-surgically diagnosed patients, 21 (70%) were treated with antifungals and 9 (30%) were followed-up without treatment. Of the 23 patients who underwent surgical treatment, 8 received additional antifungals. The proportion of patients who had radiological improvement was significantly higher in surgically diagnosed patients than non-surgically diagnosed patients (100% vs. 73%; P=0.007). However, there was no significant difference in disease progression between patients who underwent surgical resection alone and those who additionally received antifungals (P=0.999). Surgical resection was required in some patients to diagnose PC. An initial suspicion of a lung malignancy was associated with use of surgical diagnostic approaches. Surgical resection not only afforded reliable diagnoses but also effectively treated PC. There was no need for additional antifungals after complete surgical resection.


Distinct phases in the positive selection of CD8+ T cells distinguished by intrathymic migration and T-cell receptor signaling patterns.
Positive selection of CD8 T cells in the thymus is thought to be a multistep process lasting 3-4 d; however, the discrete steps involved are poorly understood. Here, we examine phenotypic changes, calcium signaling, and intrathymic migration in a synchronized cohort of MHC class I-specific thymocytes undergoing positive selection in situ. Transient elevations in intracellular calcium concentration ([Ca(2+)]i) and migratory pauses occurred throughout the first 24 h of positive selection, becoming progressively briefer and accompanied by a gradual shift in basal [Ca(2+)]i over time. Changes in chemokine-receptor expression and relocalization from the cortex to medulla occurred between 12 and 24 h after the initial encounter with positive-selecting ligands, a time frame at which the majority of thymocytes retain CD4 and CD8 expression and still require T-cell receptor (TCR) signaling to efficiently complete positive selection. Our results identify distinct phases in the positive selection of MHC class I-specific thymocytes that are distinguished by their TCR-signaling pattern and intrathymic location and provide a framework for understanding the multistep process of positive selection in the thymus.


Butein-instigated miR-186-5p-dependent modulation of TWIST1 affects resistance to cisplatin and bioenergetics of Malignant Pleural Mesothelioma cells.
Aim: Malignant pleural mesothelioma is a chemoresistant tumor, and biphasic and sarcomatoid histologies portend the worst prognosis for malignant pleural mesothelioma (MPM) patients. We obtained the microRNA expression profile of three biphasic-sarcomatoid MPM cell lines to identify commonly expressed microRNAs and evaluate the effect of butein, a chemo-sensitizing compound, on this microRNA subset. Methods: Nanostring-based microRNA profiling and analysis through the ROSALIND platform were employed to identify the commonly modulated microRNAs and their targets. MicroRNA-mimic transfection, Luciferase assay, and Western blotting were employed to show specific perturbation of TWIST1 levels by miR-186-5p. Sphere-forming assays, invasion assay, and metabolic profiling were used to assess the biological consequences of the butein-instigated miR-186-5p-mediated perturbation of TWIST1 levels. TGCA analysis was used to search for the correlation between TWIST1 and miR-186-5p levels in biphasic and epithelioid MPM specimens. Results: We identified a set of perturbed microRNAs, common to three biphasic/sarcomatoid MPM cell lines, after butein treatment. When focusing on miR-186-5p, we unraveled a butein-ignited and miR-186-5p-mediated modulation of TWIST1 levels which affected the 3D anchorage-independent growth, cisplatin resistance, invasion, and bioenergetics of the MPM cell lines tested. We showed that miR-186-5p and TWIST1 levels are anti-correlated in biphasic MPM specimens from TCGA. Conclusion: We unraveled a novel mechanism of action of butein, which attenuated the pro-tumorigenic features of MPM at least through a miR-186-5p-TWIST1 axis. We suggest that those activities converge into the chemo-sensitizing effect of this compound and may be of translational relevance.


Characterization of monoclonal antibodies that distinguish simian immunodeficiency virus isolates from each other and from human immunodeficiency virus types 1 and 2.
Two monoclonal antibodies (MAbs) against p27 and one against p17 of simian immunodeficiency virus (SIV) from rhesus macaques were produced and characterized by reacting with disrupted, viral antigens on immunoblots. Human immunodeficiency virus type 1 (HIV-1), HIV-2 and SIV isolates from sooty mangabey, stump-tailed macaque, rhesus macaque and African green monkey (SIVSM, SIVStM, SIVMAC and SIVAGM) were used for comparative analysis. The p27 monoclonal antibodies HE3 and FA2 reacted with SIVMAC and SIVSM, but not with HIV-1, HIV-2, SIVStM and SIVAGM. The p17 monoclonal antibodies reacted with SIVMAC and SIVStM, but not HIV-1, HIV-2, SIVSM and SIVAGM. The differential reactivity of these monoclonal antibodies indicated that common conserved antigenic epitopes are shared between SIVMAC and SIVSM with respect to p27 MAbs and between SIVMAC and SIVStM with respect to p17. Since these MAbs reacted differently with the SIV isolates, they are useful reagents for comparative pathogenesis studies for differentiating SIV isolates.


The effect of prolonged exposure of rats to sub-lethal dose of acetaminophen.
In this report, we studied the effect of sub-lethal doses (20mg, 30mg, 100mg, 200mg and 300mg/Kg body weight) and duration of acetaminophen given intraperitoneally (i.p) to male albino rats; on the level of pc methaemoglobin and some liver function tests: Alkaline phosphatase, free and conjugated bilirubin. The study showed that the increase in pc methaemoglobin, free and conjugated bilirubin in rats treated with acetaminophen are significantly (P less than 0.05) greater than those for the control rats and that the measured parameters increase with acetaminophen concentrations. The results also show that the free bilirubin is probably displaced from plasma albumin.


Longitudinal association between BMI at diagnosis and HIV disease progression.
Increased body mass index (BMI) has been associated with adverse health outcomes but the effect of BMI on HIV immune markers over time post-HAART is not clearly established. Data were abstracted from 396 medical records at the Ryan White Clinic in South Carolina. All HIV-infected adults who were ≥18 years of age, diagnosed between 1997 and 2010, had weight and height measured within 3 months of diagnosis and had at least one follow-up visit within 6 months of diagnosis, were eligible. The mean CD4 count was calculated for each BMI category and mixed regression analyses was used to determine the association between BMI and CD4 count over time. The overall mean BMI was 27.4 kg/m(2). Longitudinally, the mean CD4 count was 611.2 cells/mm(3) for obese individuals, 598.1 cells/mm(3) for overweight individuals and 550.5 cells/mm(3) for normal weight individuals. When compared to the normal weight category, the obese category had significantly larger increases in CD4 count (5.5 cells/mm(3), P < 0.001) versus the overweight category (-2.1 cells/mm(3), P < 0.001). HIV-infected individuals who were obese at diagnosis had larger increases in CD4 counts over time when compared to overweight individuals at diagnosis. This suggests that providers should pay closer attention to weight at diagnosis to predict the response to treatment and disease trajectory.


Changes in bone turnover markers during 14-day 6 degrees head-down bed rest.
Osteoporosis caused by exposure to microgravity represents a serious clinical concern, but the mechanisms have yet to be fully elucidated. The present research aimed to elucidate the effects of microgravity environments on bone turnover, with a specific focus on changes in bone resorption markers such as type I collagen cross-linked N-telopeptides (NTx) and deoxypyridinoline (Dpyr), for which scant data are available regarding detailed time course. Methods using 6 degrees head-down bed rest were utilized to simulate a microgravity environment. Eleven adult male volunteers underwent 6 degrees head-down bed rest for 14 days; measurements were made of serum and urine Ca concentrations, in addition to osteocalcin (OC), bone alkaline phosphatase (ALP), NTx, and Dpyr as bone turnover markers. By the end of bed rest, concentrations of bone ALP had significantly increased, but OC displayed a tendency toward decrease. Concentrations of Dpyr significantly increased from day 6, remaining elevated until the end of bed rest. Concentrations of NTx significantly increased on day 13 and at the end of bed rest. Serum and urinary concentrations of Ca increased significantly at the end of bed rest. Bone ALP represents a relatively early marker of osteoblast differentiation at the matrix maturation phase and OC is a late marker in osteoblast differentiation at the calcification phase. The present results therefore suggest an absolute increase in bone resorption and normal or reduced bone formation, together causing prominent uncoupling and rapid bone loss after simulated microgravity. Moreover, the present results suggest that bone resorption is enhanced at an early stage of exposure to microgravity environments.


Bronchitis and emphysema: importance of environmental factors and prevention.
The importance of environmental factors in Bronchitis and Emphysema is analysed in general terms, namely in which concerns the atmospheric pollutants, the tobacco smoke and occupational, socioeconomical and infectious features. The environment is also pointed out according to its relationships with endogenous factors. Personal research in the concerned areas are presented namely in the smoking and occupational fields and in studies on the deep lung. Preventive measures of Bronchitis and Emphysema are presented and briefly analysed.


A pilot randomised controlled trial of eccentric exercise to prevent hamstring injuries in community-level Australian Football.
Hamstring injuries are the most common injury sustained by Australian Football players. Eccentric training has been proposed as a potential preventative strategy. This pilot randomised controlled trial (RCT) evaluated the effectiveness of a pre-season eccentric training program for preventing hamstring injuries at the community level of Australian Football. Seven amateur clubs (n=220 players) were recruited. Players were randomised within clubs to the intervention (eccentric exercise) or control (stretching) groups and randomisation was stratified according to previous history of hamstring injury. Five exercise sessions were completed over a 12-week period, three during the pre-season and two during the first 6 weeks of the season. Compliance was recorded and players were monitored for the season to collect injury and participation data. There was no difference between the control (n=106) or intervention (n=114) groups with respect to baseline characteristics. Only 46.8% of all players completed at least two program sessions. Compliance was poorest for the intervention group. Intention-to-treat analysis suggested that players in the intervention group were not at reduced risk of hamstring injury (RR 1.2, 95% CI: 0.5, 2.8). When only control and intervention group players who participated in at least the first two sessions were analysed, 4.0% of intervention and 13.2% of control group players sustained a hamstring injury (RR 0.3, 95% CI: 0.1, 1.4; p=0.098). The findings suggest that a simple program of eccentric exercise could reduce the incidence of hamstring injuries in Australian Football but widespread implementation of this program is not likely because of poor compliance.


[Sampling and representativeness in epidemiological surveillance using sentinel sites]
This article maintains that technical issues for sampling in epidemiological surveillance require a profound review of important concepts from health theory. It is particularly neccessary to emphasize living conditions and more specifically the environments or contexts in which reproductive processes of social life take place. However, both fields require access to more complete data than those produced by traditional sources. Such an approach to epidemiological surveillance requires a review of sampling types, and this implies a new look at prevailing interpretations concerning the logical basis for inferences from samples. It becomes necessary to abandon statistical samples (even stratified ones) and to promote procedures of the "sentinel site" type. This techinique, originally applied in societies with insufficient statistical systems, can be developed in such a way as to become a substantial complement to monitoring of living conditions, even in societies with good information systems. The article suggests changes in the "sentinel site" concept, adding the requirement of "qualitative representativeness" through finalistic samples based on previous typologies of spatial/demographic units.


Adolescent brain maturation and cortical folding: evidence for reductions in gyrification.
Evidence from anatomical and functional imaging studies have highlighted major modifications of cortical circuits during adolescence. These include reductions of gray matter (GM), increases in the myelination of cortico-cortical connections and changes in the architecture of large-scale cortical networks. It is currently unclear, however, how the ongoing developmental processes impact upon the folding of the cerebral cortex and how changes in gyrification relate to maturation of GM/WM-volume, thickness and surface area. In the current study, we acquired high-resolution (3 Tesla) magnetic resonance imaging (MRI) data from 79 healthy subjects (34 males and 45 females) between the ages of 12 and 23 years and performed whole brain analysis of cortical folding patterns with the gyrification index (GI). In addition to GI-values, we obtained estimates of cortical thickness, surface area, GM and white matter (WM) volume which permitted correlations with changes in gyrification. Our data show pronounced and widespread reductions in GI-values during adolescence in several cortical regions which include precentral, temporal and frontal areas. Decreases in gyrification overlap only partially with changes in the thickness, volume and surface of GM and were characterized overall by a linear developmental trajectory. Our data suggest that the observed reductions in GI-values represent an additional, important modification of the cerebral cortex during late brain maturation which may be related to cognitive development.


Rosacea: how to recognize and treat an age-related skin disease.
Rosacea is an age-related disorder of the central portion of the facial skin whose peak onset occurs in persons in their 40s and 50s. A chronic and progressive condition of flare-ups and remissions, rosacea can be disfiguring if left untreated. Rosacea can be characterized as having three stages. Target areas for all symptoms include the cheeks, nose, chin, or forehead. Rosacea resembles a number of other dermatologic conditions, particularly acne vulgaris. The combination of oral and topical antibiotic therapy usually brings about remission. The key is to recognize the early signs and clinical picture so that accurate diagnosis can be made and therapy and counseling instituted.


Exenatide as a weight-loss therapy in extreme pediatric obesity: a randomized, controlled pilot study.
The objective of this pilot study was to evaluate the effects of exenatide on BMI (primary endpoint) and cardiometabolic risk factors in nondiabetic youth with extreme obesity. Twelve children and adolescents (age 9-16 years old) with extreme obesity (BMI ≥1.2 times the 95th percentile or BMI ≥35 kg/m(2)) were enrolled in a 6-month, randomized, open-label, crossover, clinical trial consisting of two, 3-month phases: (i) a control phase of lifestyle modification and (ii) a drug phase of lifestyle modification plus exenatide. Participants were equally randomized to phase-order (i.e., starting with control or drug therapy) then crossed-over to the other treatment. BMI, body fat percentage, blood pressure, lipids, oral glucose tolerance tests (OGTT), adipokines, plasma biomarkers of endothelial activation, and endothelial function were assessed at baseline, 3-, and 6-months. The mean change over each 3-month phase was compared between treatments. Compared to control, exenatide significantly reduced BMI (-1.7 kg/m(2), 95% confidence interval (CI) (-3.0, -0.4), P = 0.01), body weight (-3.9 kg, 95% CI (-7.11, -0.69), P = 0.02), and fasting insulin (-7.5 mU/l, 95% CI (-13.71, -1.37), P = 0.02). Significant improvements were observed for OGTT-derived insulin sensitivity (P = 0.02) and β-cell function (P = 0.03). Compliance with the injection regimen was excellent (≥94%) and exenatide was generally well-tolerated (the most common adverse event was mild nausea in 36%). These preliminary data suggest that exenatide should be evaluated in larger, well-controlled trials for its ability to reduce BMI and improve cardiometabolic risk factors in youth with extreme obesity.


Development of a mouse model of ischemic osteonecrosis.
Availability of a reliable mouse model of ischemic osteonecrosis could accelerate the development of novel therapeutic strategies to stimulate bone healing after ischemic osteonecrosis; however, no mouse model of ischemic osteonecrosis is currently available. To develop a surgical mouse model of ischemic osteonecrosis, we asked, (1) if the blood vessels that contribute to the blood supply of the distal femoral epiphysis are cauterized, can we generate an osteonecrosis mouse model; (2) what are the histologic changes observed in this mouse model, and (3) what are the morphologic changes in the model. We performed microangiography to identify blood vessels supplying the distal femoral epiphysis in mice, and four vessels were cauterized using microsurgical techniques to induce ischemic osteonecrosis. Histologic assessment of cell death in the trabecular bone was performed using terminal deoxynucleotidyl transferase mediated dUTP nick-end labeling (TUNEL) and counting the empty lacunae in three serial sections. Quantitation of osteoclast and osteoblast numbers was performed using image analysis software. Morphologic assessments of the distal femoral epiphysis for deformity and for trabecular bone parameters were performed using micro-CT. We identified four blood vessels about the knee that had to be cauterized to induce total ischemic osteonecrosis of the distal femoral epiphysis. Qualitative assessment of histologic sections of the epiphysis showed a loss of nuclear staining of marrow cells, disorganized marrow structure, and necrotic blood vessels at 1 week. By 2 weeks, vascular tissue invasion of the necrotic marrow space was observed with a progressive increase in infiltration of the necrotic marrow space with the vascular tissue at 4 and 6 weeks. TUNEL staining showed extensive cell death in the marrow and trabecular bone 24 hours after the induction of ischemia. The mean percent of TUNEL-positive osteocytes in the trabecular bone increased from 2% ± 1% in the control group to a peak of 98% ± 3% in the ischemic group 1 week after induction of ischemia (mean difference, 96%; 95% CI, 81%-111%; p < 0.0001). The mean percent of empty lacunae increased from 1% ± 1% in the control group to a peak of 78% ± 15% in the ischemic group at 4 weeks (mean difference, 77%; 95% CI, 56%-97%; p < 0.0001). Quantitative analysis showed that the mean number of osteoclasts per bone surface was decreased in the ischemic group at 1, 2, and 4 weeks (p < 0.0001, < 0.0001, and p = 0.02, respectively) compared with the control group. The mean number of osteoclasts increased to a level similar to that of the control group at 6 weeks (p = 0.23). The numbers of osteoblasts per bone surface were decreased in the ischemic group at 1, 2 and 4 weeks (p < 0.0001 for each) compared with the numbers in the control group. The mean number of osteoblasts also increased to a level similar to that of the control group at 6 weeks (p = 0.91). Mean bone volume percent assessed by micro-CT was lower in the ischemic group compared with the control group from 2 to 6 weeks. The mean differences in the percent bone volume between the control and ischemic groups at 2, 4, and 6 weeks were 5.5% (95% CI, 0.9%-10.2%; p = 0.01), 5.3% (95% CI, 0.6%-9.9%; p = 0.02), and 6.0% (95% CI, 1.1%-10.9%; p = 0.008), respectively. A deformity of the distal femoral epiphysis was observed at 6 weeks with the mean epiphyseal height to width ratio of 0.74 ± 0.03 in the control group compared with 0.66 ± 0.06 in the ischemic group (mean difference, 0.08; 95% CI, 0.00-0.16; p = 0.03). We developed a novel mouse model of ischemic osteonecrosis that produced extensive cell death in the distal femoral epiphysis which developed a deformity with time. The new mouse model may be a useful tool to test potential therapeutic strategies to improve bone healing after ischemic osteonecrosis.


Tetrasomy 18p: The challenges of noninvasive prenatal testing and combined test.
Circulating cell-free DNA, having no procedural risk of miscarriage, is the most suitable sample for a noninvasive prenatal testing (NIPT). Here we report on a boy, who came to our attention for hypotonia and psychomotor delay when he was 16 months old. During the pregnancy his mother performed a NIPT that resulted compatible with the presence of trisomy 18. A confirmatory invasive procedure has been proposed, but not performed, because the family preferred to follow a conservative line. A series of ultrasound excluded the presence of any major malformations. Genetic tests, performed after birth, revealed the presence of a tetrasomy 18p with an extra isochromosome 18p. Our report wants to underline the importance of an invasive procedure and consequent cytogenetic analysis in case of NIPT results indicating autosomal trisomies because under it may hide the presence of other structural chromosomal anomalies. These conditions are normally not visible at prenatal ultrasound or using combined test (CT) and the only identifiable not invasive sign could be the results of high risk at NIPT.


One-layer colonic anastomosis with polyglycolic acid (Dexon) suture: a 3-year prospective audit.
Fear of leakage has inhibited many surgeons from performing one-layer anastomosis with a continuous absorbable suture for the outer layer. Ninety-three one-layer colonic anastomoses were performed using polyglycolic acid sutures in 92 patients. Mortality was low (1.1%) and intra-abdominal septic complications occurred in only 4 patients (4.4%). Superficial wound infections occurred in a further 6 patients (6.5%). The mean postoperative hospital stay was 13.2 d with more than 79% being discharged in 15 d.


COVID-19 Pandemic Imperils Weather Forecast.
Weather forecasts play essential parts in economic activity. Assimilation of meteorological observations from aircraft improves forecasts greatly. However, global lockdown during the COVID-19 pandemic (March to May 2020) has eliminated 50-75% aircraft observations and imperiled weather forecasting. Here, we verify global forecasts against reanalysis to quantify the impact of the pandemic. We find a large deterioration in forecasts of surface meteorology over regions with busy air flights, such as North America, southeast China, and Australia. Forecasts over remote regions are also substantially worse during March to May 2020 than 2017-2019, and the deterioration increases for longer-term forecasts. This could handicap early warning of extreme weather and cause additional economic damage on the top of that from the pandemic. The impact over Western Europe is buffered by the high density of conventional observations, suggesting that introduction of new observations in data-sparse regions would be needed to minimize the impact of global emergencies on weather forecasts.


Nottingham prognostic index plus (NPI+) predicts risk of distant metastases in primary breast cancer.
The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p > 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p > 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer.


Influence of fungal infection and wounding on contents and enantiomeric compositions of monoterpenes in phloem of Pinus sylvestris.
To identify chemical resistant markers induced by fungal or mechanical injury, young trees of Scots pine (Pinus sylvestris) were subjected to inoculations of blue stain fungi associated with the pine shoot beetles Tomicus piniperda and T. minor. Among the 20 trees selected for chemical analyses, 16 were divided into four groups: one as control and three were pretreated by wounding only, or by inoculation with either the blue stain fungus Leptographium wingfieldii or Ophiostoma canum. Four wk after pretreatment, all 16 pretreated trees were mass-inoculated with L. wingfieldii. The absolute and relative amounts, as well as the enantiomeric compositions of monoterpene hydrocarbons in the phloem, were determined via a small sample of the phloem before and after the pretreatment and mass inoculation, by using two-dimensional gas chromatography (2D GC) and GC-mass spectrometry (MS). After mass inoculation, the absolute amounts of most of the monoterpenes decreased in the phloem sampled >20 cm from the fungal infection, and were higher in the phloem sampled within the infected reaction zone. The relative amounts of both (-)-beta-pinene and (-)-limonene increased in phloem samples taken >20 cm above the fungal inoculation in the preinoculated trees compared with phloem sampled from the remaining four control trees. The enantiomeric compositions of beta-pinene and limonene changed, after fungal growth, at defined distances from the inoculation site: the proportion of the (-)-enantiomers was highest in the phloem sampled >20 cm from the fungal inoculation. Four wk after pretreatment, monoterpene production in the phloem at the site of inoculation was more enhanced by L. wingfieldii than by O. canum. However, the different virulence levels of the fungi did not affect the enantiomeric composition of the monoterpenes. The biosynthesis of monoterpene enantiomers is discussed in relation to induced pathogen resistance.


Neurobehavioral teratogenicity of perfluorinated alkyls in an avian model.
Perfluorinated alkyls are widely-used agents that accumulate in ecosystems and organisms because of their slow rate of degradation. There is increasing concern that these agents may be developmental neurotoxicants and the present study was designed to develop an avian model for the neurobehavioral teratogenicity of perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS). Fertilized chicken eggs were injected with 5 or 10mg/kg of either compound on incubation day 0. On the day of hatching, imprinting behavior was impaired by both compounds. We then explored underlying mechanisms involving the targeting of protein kinase C (PKC) isoforms (alpha, beta, gamma) in the intermedial part of the hyperstriatum ventrale, the region most closely associated with imprinting. With PFOA exposure, cytosolic PKC concentrations were significantly elevated for all three isoforms; despite the overall increase in PKC expression, membrane-associated PKC was unaffected, indicating a defect in PKC translocation. In contrast, PFOS exposure evoked a significant decrease in cytosolic PKC, primarily for the beta and gamma isoforms, but again without a corresponding change in membrane-associated enzyme; this likely partial, compensatory increases in translocation to offset the net PKC deficiency. Our studies indicate that perfluorinated alkyls are indeed developmental neurotoxicants that affect posthatch cognitive performance but that the underlying synaptic mechanisms may differ substantially among the various members of this class of compounds, setting the stage for disparate outcomes later in life.


Association between the risk of falls and osteoporotic fractures in patients with type 2 diabetes mellitus.
Diabetes mellitus is associated with an increased risk of falls, which increases the incidence of osteoporotic fractures and accordingly decreases quality of life. However, the association between fall risk and diabetic complications is not completely understood. Therefore, the aim of this study was to examine the association between fall risk and osteoporotic fractures in patients with type 2 diabetes mellitus (T2DM). We enrolled 194 Japanese patients with T2DM and assessed their fall risk using a brief interview form that included five items covering physical and social aspects of functioning and environmental factors. We examined the associations between fall risk and the presence of diabetic complications, such as neuropathy, retinopathy, nephropathy, cardiovascular disease, cerebrovascular disease, peripheral artery disease (PAD), and osteoporotic fractures (including any fracture and vertebral fractures only). In the multivariate logistic regression analysis, a longer history of T2DM, the presence of neuropathy and PAD, and a history of any fractures were significantly and positively associated with the risk of falls. On the other hand, a lower body mass index, the presence of neuropathy, and the risk of falls were independently and positively associated with the risk of any fracture. When fractures were limited to vertebral fractures only, the association with the risk of falls remained significant. We found that the risk of falls and osteoporotic fractures were associated in patients with T2DM and that a brief screening test of the risk of falls was useful for assessing the risk of osteoporotic fractures.


Deep learning in histopathology: the path to the clinic.
Machine learning techniques have great potential to improve medical diagnostics, offering ways to improve accuracy, reproducibility and speed, and to ease workloads for clinicians. In the field of histopathology, deep learning algorithms have been developed that perform similarly to trained pathologists for tasks such as tumor detection and grading. However, despite these promising results, very few algorithms have reached clinical implementation, challenging the balance between hope and hype for these new techniques. This Review provides an overview of the current state of the field, as well as describing the challenges that still need to be addressed before artificial intelligence in histopathology can achieve clinical value.


Oscillatory regimes in a mosquito population model with larval feedback on egg hatching.
Understanding mosquitoes life cycle is of great interest presently because of the increasing impact of vector borne diseases in several countries. There is evidence of oscillations in mosquito populations independent of seasonality, still unexplained, based on observations both in laboratories and in nature. We propose a simple mathematical model of egg hatching enhancement by larvae which produces such oscillations that conveys a possible explanation. We propose both a theoretical analysis, based on slow-fast dynamics and Hopf bifurcation, and numerical investigations in order to shed some light on the mechanisms at work in this model.


Taxonomic and molecular identification of bakernema, criconema, hemicriconemoides, ogma and xenocriconemella species (nematoda: criconematidae).
Populations of Bakernema inaequale, C. petasum, C. sphagni, C. mutabile, Ogma octangulare, Xenocriconemella macrodora and Hemicriconemoides chitwoodi were identified and re-described from different geographical areas in the continental United States and molecularly characterized. Two new species of spine nematodes Criconema arkaense n. sp. from Washington County and Lee County, Arkansas and Criconema warrenense n. sp from Warren, Bradley County, Arkansas are also described and named. Criconema arkaense is characterize by having a conspicuous lip region offset from the body with two annuli, short rounded tail with a thin cuticular sheath and subterminal anus. Criconema warrenense n. sp. has two lip region annuli about the same width, first annulus directed posteriorly, separated by a narrow neck annulus and a short conoid tail, unilobed non-folded annulus. The molecular characterization of Criconema arkaense and Criconema warrenense using ITS1 rDNA gene sequence and the molecular phylogenetic relationships of these new species along with the known spines nematodes are provided.


Polymeric Materials Obtained by Extrusion and Injection Molding from Lignocellulosic Agroindustrial Biomass.
This review presents the advances in polymeric materials achieved by extrusion and injection molding from lignocellulosic agroindustrial biomass. Biomass, which is derived from agricultural and industrial waste, is a renewable and abundant feedstock that contains mainly cellulose, hemicellulose, and lignin. To improve the properties and functions of polymeric materials, cellulose is subjected to a variety of modifications. The most common modifications are surface modification, grafting, chemical procedures, and molecule chemical grafting. Injection molding and extrusion technologies are crucial in shaping and manufacturing polymer composites, with precise control over the process and material selection. Furthermore, injection molding involves four phases: plasticization, injection, cooling, and ejection, with a focus on energy efficiency. Fundamental aspects of an injection molding machine, such as the motor, hopper, heating units, nozzle, and clamping unit, are discussed. Extrusion technology, commonly used as a preliminary step to injection molding, presents challenges regarding fiber reinforcement and stress accumulation, while lignin-based polymeric materials are challenging due to their hydrophobicity. The diverse applications of these biodegradable materials include automotive industries, construction, food packaging, and various consumer goods. Polymeric materials are positioned to offer even bigger contributions to sustainable and eco-friendly solutions in the future, as research and development continues.


The kinetics of effector binding to phosphofructokinase. The binding of Mg2+-1,N6-ethenoadenosine triphosphate to the catalytic site.
1. The binding of the fluorescent ATP analogue, Mg2+-1,N6-etheno-ATP, to the catalytic site of rabbit skeletal muscle phosphofructokinase has been studied by stopped-flow fluorimetry [Roberts & Kellet (1979) Biochem. J. 183, 349--360]. 2. Binding of Mg2+-1,N6-etheno-ATP to the catalytic site is consistent with a two-step mechanism of the type: (formula: see text); in which the diffusion-controlled binding of ligand, L, is accompanied by prior interconversion of enzyme from one form, E, to another, E. 3. The allosteric activators, phosphate and cyclic AMP, which promote an R-type conformation, appear to stabilize slightly different conformations, R and R' respectively. 4. The binding of Mg2+-1,N6-etheno-ATP to the catalytic site is strongly affected by its binding to the inhibitory site. The rate constant for the displacement of Mg2+-1,N6-ethenol-ATP from the catalytic site, k32, is 470 +/- 35 s-1 for the R' conformation, whereas it is 6.0 +/- 0.09 s-1 for the T conformation induced by binding of Mg2+-1,N6-ethenol-ATP to the inhibitory site.


Activin signaling balances proliferation and differentiation of ovarian niche precursors and enables adjustment of niche numbers.
How the numbers of niches and resident stem cells within a particular organ are determined during development and how they may be modulated or corrected is a question with significant medical implications. In the larval ovary of Drosophila melanogaster, somatic precursors for niches, and germ cells that will become germline stem cells, co-develop. Somatic precursors proliferate during the first 3 days of larval development. By mid-third instar, adult terminal filament (TF) (part of the germline stem cell niche) cells first appear, and differentiation terminates 24 h later when 16-20 TFs fully form. The developmental sequence responsible for TF cell determination and final TF numbers is only partially understood. We show that TF formation proceeds through several, hitherto uncharacterized stages, which include an early exit from the cell cycle to form TF precursors and two steps of cell shape change to form the mature TF cells. The Activin receptor Baboon (Babo) is required for somatic precursor cell proliferation and therefore determines the pool of TF precursors available for TF differentiation. During the final differentiation stage, Babo facilitates TF and germ cell differentiation, and promotes the accumulation of Broad-Z1, which is also a target of the steroid hormone ecdysone. Epistasis analysis shows that Activin controls cell proliferation in an ecdysone-independent manner and TF differentiation by affecting ecdysone targets. We propose that this mode of function allows Activin to balance proliferation and differentiation, and to equilibrate niche numbers. These results suggest a novel model for how niche numbers are corrected during development.


Grandmultiparas in modern obstetrics.
The objective of this study was to compare incidence of antenatal and intrapartum complications among women who had previously delivered five or more times (grandmultiparas cases, 155) with that of age-matched women with two to three previous deliveries (multiparas controls, 155) from 1998 to 2003. Grandmultiparity was associated with a low socioeconomic status, higher incidence of smoking, and a higher body mass index. Grandmultiparas had approximately 2-fold increased risk of gestational diabetes, hypertensive disorders, malpresentation, and preterm delivery, and a 3-fold increased risk of abruption; none reached statistical significance. No significant differences were found in antepartum hemorrhage, anemia, postdatism, polyhydramnios, or placenta previa. Intrapartum complications (labor induction, nonreassuring fetal heart, primary cesarean delivery, and intrapartum fever) were similar; however, operative vaginal delivery was significantly lower in grandmultiparas cases. Both groups were similar regarding birthweight, macrosomia, intrauterine growth restriction, Apgar scores, and stillbirth rates. Our study shows a trend toward an increased risk of adverse obstetrical outcome in grandmultiparas compared with multiparas independent of maternal age.


Effect of mannitol on local cerebral blood flow after temporary complete cerebral ischemia in rats.
The effects of pretreatment with mannitol on local cerebral blood flow (CBF) after permanent or temporary global cerebral ischemia were evaluated with 14C-iodoantipyrine autoradiography in rats under halothane-N2O endotracheal anesthesia. Blood pressure, pulse rate, arterial blood gas levels, and electroencephalographic (EEG) tracings were monitored throughout the experiments. After permanent occlusion of the basilar artery and both external carotid and pterygopalatine arteries, severe global ischemia was induced by permanent occlusion of the common carotid arteries (CCA's) or by a 30-minute temporary CCA occlusion followed by 5 minutes of reperfusion. Intravenous mannitol (25%, 1 gm/kg) or saline solution was administered 5 minutes before occlusion of the CCA's. Cerebral blood flow was measured in 24 anatomical regions. The EEG tracings flattened within 2 to 3 minutes after the onset of ischemia, and no recovery was observed during reperfusion. In the mannitol-treated rats and the saline-treated controls, autoradiographic studies after permanent occlusion showed no CBF in the forebrain or cerebellum, although brain-stem and spinal cord CBF values were normal. After 5 minutes of reperfusion, CBF in the cortex, basal ganglia, and white matter was 100% to 200% higher in mannitol-treated rats and 50% to 100% higher in saline-injected rats than in the nonischemic anesthetized control group. Heterogeneously distributed areas of no-reflow were seen in all saline-injected rats but were observed in none of the mannitol-treated rats. Pretreatment with mannitol prevented postischemic obstruction of the microcirculation during 5 minutes of recirculation after 30 minutes of severe temporary ischemia, but the EEG signals did not recover. Further studies of the functional and morphological responses to longer periods of postischemic recirculation are needed to verify the extent to which these mannitol-induced effects are protective.


Autosomal dominant retinitis pigmentosa-associated gene PRPF8 is essential for hypoxia-induced mitophagy through regulating ULK1 mRNA splicing.
Aged and damaged mitochondria can be selectively degraded by specific autophagic elimination, termed mitophagy. Defects in mitophagy have been increasingly linked to several diseases including neurodegenerative diseases, metabolic diseases and other aging-related diseases. However, the molecular mechanisms of mitophagy are not fully understood. Here, we identify PRPF8 (pre-mRNA processing factor 8), a core component of the spliceosome, as an essential mediator in hypoxia-induced mitophagy from an RNAi screen based on a fluorescent mitophagy reporter, mt-Keima. Knockdown of PRPF8 significantly impairs mitophagosome formation and subsequent mitochondrial clearance through the aberrant mRNA splicing of ULK1, which mediates macroautophagy/autophagy initiation. Importantly, autosomal dominant retinitis pigmentosa (adRP)-associated PRPF8 mutant R2310K is defective in regulating mitophagy. Moreover, knockdown of other adRP-associated splicing factors, including PRPF6, PRPF31 and SNRNP200, also lead to ULK1 mRNA mis-splicing and mitophagy defects. Thus, these findings demonstrate that PRPF8 is essential for mitophagy and suggest that dysregulation of spliceosome-mediated mitophagy may contribute to pathogenesis of retinitis pigmentosa.


Multi-micronutrient supplementation during pregnancy for prevention of maternal anaemia and adverse birth outcomes in a high-altitude area: a prospective cohort study in rural Tibet of China.
Anaemia during pregnancy, characterised by Hb <110 g/l, is a specific risk factor for adverse maternal and perinatal outcomes in developing countries. The objective of this study was to determine the effectiveness of daily antenatal supplementation with multiple micronutrients (MMN) compared with folic acid (FA) on the occurrence of anaemia among pregnant women and their infants' health in a high-altitude area. A prospective cohort study was carried out in two rural counties in Tibet from 2007 to 2012. A total of 1149 eligible pregnant women were allocated daily supplementation with FA in one county and MMN containing a recommended allowance of twenty-three vitamins and minerals in another county starting ≤24 weeks of gestation and continuing until delivery. Compared with the FA group, prenatal supplementation with MMN was significantly associated with reduced odds of anaemia in the third trimester. This was demonstrated in the primary outcome, with an adjusted OR (AOR) of 0·63; 95 % CI 0·45, 0·88 and P=0·007 and also reduced odds of preterm delivery (AOR: 0·31; 95 % CI 0·15, 0·61; P=0·001). There was no difference between MMN and FA groups in mean birth weight (adjusted mean difference: 36·78; 95 % CI -19·42, 92·98 g; P=0·200), whereas MMN supplementation significantly reduced the odds of low-birth weight (LBW) babies (AOR: 0·58; 95 % CI 0·36, 0·91; P=0·019). In conclusion, the antenatal MMN supplementation in rural Tibet is associated with a reduction of maternal anaemia in the third trimester, and may potentially decrease the risk of preterm delivery and LBW babies.


A density function theory study on the NO reduction on nitrogen doped graphene.
The mechanisms for the catalytic reduction of NO on the metal-free nitrogen doped graphene (NG) support are investigated using the density function theory (DFT) calculations both with and without the van der Waals (vdW) correction. The results indicate that the dimer mechanism is more facile than the direct decomposition mechanism. In the dimer mechanism, a three-step reaction is identified: (i) the coupling of two NO molecules into a (NO)2 dimer, followed by (ii) the dissociation of the (NO)2 dimer into N2O + Oad, then (iii) the O adatom is taken away easily by the subsequent NO. Once the NO2 is desorbed, the remaining N2O can be reduced readily by NO on NG. The reaction processes are also confirmed from the first principles molecular dynamics simulations. The results suggest that the NG is an efficient metal-free catalyst for catalytic reduction of NO.


Sex differences in reporting of concussion symptoms in adults.
Objective: To examine differences in concussion symptom reporting between female and male adults considering current psychological symptoms such as anxiety and depression and pre-injury factors in order to identify sex differences which may guide treatment efforts. Method: This prospective study is part of the North Texas Concussion Registry (ConTex). Subjects (N = 132) age 19 to 78 years had sustained a concussion within 30 days of clinic visit. The independent variable was sex and covariates included age, ethnicity, current anxiety and depression ratings, history of attention deficit disorder, history of headache/migraine, and time to clinic. The dependent variables were 22 post-concussion symptoms as measured by the Sport Concussion Assessment Tool-5 Post-Concussion Symptom Scale. Results: Analysis of covariance and ordinal logistic regression results both revealed that females had a greater likelihood of reporting increased symptom severity for 15/22 concussion symptoms. The largest risk ratios (effect size) in symptom reporting between sexes (higher symptoms in females) included: feeling more emotional 4.05 (0.72), fatigue or low energy 4.05 (0.72), sensitivity to light 3.74 (0.69), headache 3.65 (0.57), balance problems 3.31 (0.53), pressure in head 3.06 (0.51), and neck pain 2.97 (0.60). Conclusions: Adult females in our sample reported higher levels of many concussion symptoms than males and showed an increased risk of developing these same symptoms following concussion. Examination of the magnitude of sex difference in concussion symptom reporting will better inform medical staff to anticipate and address symptoms that may present greater challenges for adult females.


Seasonal variation of fluoride intake by children in a subtropical region.
Since the optimum fluoride concentration in drinking water established for temperate countries has been considered not to be appropriate for tropical and subtropical climates, this study was conducted in Piracicaba, a subtropical, optimally fluoridated Brazilian community. The daily fluoride intake by 23 children (aged 20-30 months) from diet (liquids and solids) during the four seasons of the year was evaluated. Duplicate-plate samples of foods and beverages were collected for 2 days in each season of the year. The difference of fluoride intake during the 4 seasons was not statistically significant (p>0.05). However, the adjusted data, based on the volume of the diet collected and on the assumption of a constant fluoride concentration in the drinking water, showed that fluoride intake during spring-summer was statistically higher than that observed during the fall-winter seasons (p<0.05). The fluoride dose to which the children were submitted during the hot seasons would be 19% higher than that found during the cold ones. Although this dose difference would not to be a concern for a subtropical area, it could be relevant for a region with a genuine tropical climate.


Antiphospholipid (Hughes) syndrome 40th anniversary.
This article is a celebration of the 40th anniversary of APS, a disease that appears to affect one in 2000 people. The quality of life of patients affected has improved significantly as a result of early diagnosis and effective treatment.


This review was written in response to the author's receipt of the JSBBA Award for Young Scientists in 2022.
Strigolactones (SLs) are a class of terpenoid lactones initially identified as seed germination stimulants for root parasitic plants more than 50 years ago. Long after this initial discovery, SLs were re-characterized as the symbiotic signals for arbuscular mycorrhizal fungi that supply inorganic nutrients, such as phosphate, to their host plants. In 2008, SLs were found to be endogenous plant hormones that regulate shoot branching in plants. The discovery of SLs as a new class of plant hormones has significantly advanced research in this field. Studies over the past 15 years have elucidated almost the entire pathway of SL biosynthesis and the overall mechanism of its signalling. This review summarizes research on the SL biosynthetic pathway, and the current state of knowledge of the SL perception mechanism.


Urban malaria: primary caregivers' knowledge, attitudes, practices and predictors of malaria incidence in a cohort of Ugandan children.
To assess malaria-related knowledge, attitude and practices (KAP) among primary caregivers, to identify associations between primary caregivers' characteristics and positive KAP towards malaria, and to identify independent predictors of childhood malaria incidence in an urban setting. Children aged 6 months to 5 years living in Kampala, Uganda were enrolled as part of a longitudinal study on antimalarial therapy. Primary caregivers of 307 children were interviewed and information was collected on demographics, malaria-related KAP, environmental and household factors. Malaria incidence was measured prospectively using passive surveillance. A total of 90% of respondents reported mosquitoes and/or malaria as the cause of fever. Caregivers reported that if their child had fever, 63% would go to a clinic or hospital as their first action and 97% as their first or second action. Only 38% knew that chloroquine was the recommended first-line treatment for malaria and 29% knew the correct dose. Preventive measures for malaria were reported in 45% of households but only 25% reported using bednets. Higher levels of education for the caregiver were associated with positive malaria-related KAP. Malaria incidence varied widely. The following were independent predictors of malaria incidence: (1). Children aged 24-41 months at enrolment had a higher incidence of malaria. (2). Reported bednet or chemoprophylaxis use reduced the incidence of malaria. (3). A child's place of residence was associated with incidence. (4). Children from households using open water sources had a higher incidence than those using closed sources. Primary caregivers were knowledgeable about malaria and used modern health care facilities but knew less about the proper administration of antimalarials and had limited use of preventive measures. Malaria incidence was associated with child's age at enrolment, geography, source of water and the use of preventive measures.


A novel artificial intelligence protocol for finding potential inhibitors of acute myeloid leukemia.
There is currently no effective treatment for acute myeloid leukemia, and surgery is also ineffective as an important treatment for most tumors. Rapidly developing artificial intelligence technology can be applied to different aspects of drug development, and it plays a key role in drug discovery. Based on network pharmacology and virtual screening, candidates were selected from the molecular database. Nine artificial intelligence algorithm models were used to further verify the candidates' potential. The 350 training results of the deep learning model showed higher credibility, and the R-square of the training set and test set of the optimal model reached 0.89 and 0.84, respectively. The random forest model has an R-square of 0.91 and a mean square error of only 0.003. The R-square of the Adaptive Boosting model and the Bagging model reached 0.92 and 0.88, respectively. Molecular dynamics simulation evaluated the stability of the ligand-protein complex and achieved good results. Artificial intelligence models had unearthed the promising candidates for STAT3 inhibitors, and the good performance of most models showed that they still had practical value on small data sets.


Finite-time adiabatic processes: Derivation and speed limit.
Obtaining adiabatic processes that connect equilibrium states in a given time represents a challenge for mesoscopic systems. In this paper, we explicitly show how to build these finite-time adiabatic processes for an overdamped Brownian particle in an arbitrary potential, a system that is relevant at both the conceptual and the practical level. This is achieved by jointly engineering the time evolutions of the binding potential and the fluid temperature. Moreover, we prove that the second principle imposes a speed limit for such adiabatic transformations: there appears a minimum time to connect the initial and final states. This minimum time can be explicitly calculated for a general compression or decompression situation.


Arylation and alkenylation of activated alkyl halides using sulfonamides.
A variety of quaternary aryl amino acid derivatives can be synthesised using tandem SN2/Smiles rearrangement chemistry involving aryl sulfonamides and α-chloro carbonyl compounds. The reaction harnesses a sulfur dioxide extrusion pathway to construct a C-N and C-Caryl bond under simple conditions with no requirement for organometallics or transition metal catalysts. The reaction is also successful for alkenyl sulfonamides, producing sterically congested quaternary alkene amino acid derivatives.


Parent-child resemblance in weight status and its correlates in the United States.
Few studies have examined parent-child resemblance in body weight status using nationally representative data for the US. We analyzed Body Mass Index (BMI), weight status, and related correlates for 4,846 boys, 4,725 girls, and their parents based on US nationally representative data from the 2006 and 2007 Medical Expenditure Panel Survey (MEPS). Pearson partial correlation coefficients, percent agreement, weighted kappa coefficients, and binary and multinomial logistic regression were used to examine parent-child resemblance, adjusted for complex sampling design. Pearson partial correlation coefficients between parent and child's BMI measures were 0.15 for father-son pairs, 0.17 for father-daughter pairs, 0.20 for mother-son pairs, and 0.23 for mother-daughter pairs. The weighted kappa coefficients between BMI quintiles of parent and child ranged from -0.02 to 0.25. Odds ratio analyses found children were 2.1 (95% confidence interval (CI): 1.6, 2.8) times more likely to be obese if only their father was obese, 1.9 (95% CI: 1.5, 2.4) times more likely if only their mother was obese, and 3.2 (95% CI: 2.5, 4.2) times more likely if both parents were obese. Parent-child resemblance in BMI appears weak and may vary across parent-child dyad types in the US population. However, parental obesity status is associated with children's obesity status. Use of different measures of parent-child resemblance in body weight status can lead to different conclusions.


Studies on the chick-lethal toxin of Eecherichia coli.
A toxin which is lethal for two week old chicks has been recovered from strains of Escherichia coli O78:K80 of bovine and avian origin and from avian isolates of serogroups O2, O45 and O109. The toxin is heat-labile, antigenic, high in protein, inactivated by pronase, trypsin, amylase, and pancreatic lipase. The toxin may be precipitated by ammonium sulfate or TCA treatment from the supernatant obtained by repeated centrifugation of sonicated cells. Considerable purification has been obtained by column chromatography using Sepharose 6B.


Evolution of the aging brain transcriptome and synaptic regulation.
Alzheimer's disease and other neurodegenerative disorders of aging are characterized by clinical and pathological features that are relatively specific to humans. To obtain greater insight into how brain aging has evolved, we compared age-related gene expression changes in the cortex of humans, rhesus macaques, and mice on a genome-wide scale. A small subset of gene expression changes are conserved in all three species, including robust age-dependent upregulation of the neuroprotective gene apolipoprotein D (APOD) and downregulation of the synaptic cAMP signaling gene calcium/calmodulin-dependent protein kinase IV (CAMK4). However, analysis of gene ontology and cell type localization shows that humans and rhesus macaques have diverged from mice due to a dramatic increase in age-dependent repression of neuronal genes. Many of these age-regulated neuronal genes are associated with synaptic function. Notably, genes associated with GABA-ergic inhibitory function are robustly age-downregulated in humans but not in mice at the level of both mRNA and protein. Gene downregulation was not associated with overall neuronal or synaptic loss. Thus, repression of neuronal gene expression is a prominent and recently evolved feature of brain aging in humans and rhesus macaques that may alter neural networks and contribute to age-related cognitive changes.


Research Misconduct Investigations in China's Science Funding System.
As stewards of public money, government funding agencies have the obligation and responsibility to uphold the integrity of funded research. Despite an increasing amount of empirical studies examining research-related misconduct, a majority of these studies focus on retracted publications. How agencies spot funding-relevant wrongdoing and what sanctions the offenders face remain largely unexplored. This is particularly true for public funding agencies in emerging science powers. To amend this oversight, we retrieved and analyzed all publicized investigation results from China's largest basic research funding agency over the period from 2005 to 2021. Our findings reveal that both the "police patrol" and "fire alarm" approaches are used to identify misconduct and deter funding-related fraud in China. The principal triggers for investigations are journal article retractions, whistleblowing, and plagiarism detection software. Among the six funding-related misconduct types publicized and punished, the top three are: (1) fraudulent papers, (2) information fabrication and/or falsification in the research proposal, and (3) proposal plagiarism. The most common administrative sanctions are debarment and reclamation of grants. This article argues that more systematic research and cooperation among stakeholders is needed to cultivate research integrity in emerging science powers like China. Specific training and education should be provided for young scientists to help them avoid the pitfall of academic misconduct.


[Effect of calmodulin antagonists on the membrane potential and intracellular Ca2+ stores in endothelial cells].
The role of calmodulin in electrical and Ca2+ signalling in intact rat aortic endothelial cells has been investigated. Calmodulin antagonists released Ca2+ from acetylcholine-sensitive and insensitive intracellular Ca2+ stores activated Ca(2+)-activated K+ channels and hyperpolarized endothelial cells. These findings indicate that calmodulin is involved in the regulation of intracellular Ca2+ stores in endothelial cells and is an essential agent for maintaining them in the Ca(2+)-loaded state.


Transcription-controlled gene therapy against tumor angiogenesis.
A major drawback of current approaches to antiangiogenic gene therapy is the lack of tissue-specific targeting. The aim of this work was to trigger endothelial cell-specific apoptosis, using adenoviral vector-mediated delivery of a chimeric death receptor derived from the modified endothelium-specific pre-proendothelin-1 (PPE-1) promoter. In the present study, we constructed an adenovirus-based vector that targets tumor angiogenesis. Transcriptional control was achieved by use of a modified endothelium-specific promoter. Expression of a chimeric death receptor, composed of Fas and TNF receptor 1, resulted in specific apoptosis of endothelial cells in vitro and sensitization of cells to the proapoptotic effect of TNF-alpha. The antitumoral activity of the vectors was assayed in two mouse models. In the model of B16 melanoma, a single systemic injection of virus to the tail vein caused growth retardation of tumor and reduction of tumor mass with central tumor necrosis. When the Lewis lung carcinoma lung-metastasis model was applied, i.v. injection of vector resulted in reduction of lung-metastasis mass, via an antiangiogenic mechanism. Moreover, by application of the PPE-1-based transcriptional control, a humoral immune response against the transgene was avoided. Collectively, these data provide evidence that transcriptionally controlled, angiogenesis-targeted gene therapy is feasible.


Complex adaptive chronic care.
The Chronic Care Model (CCM) is widely taken up as the universal operational framework for redesigning health systems to address the increasing chronic disease burden of an ageing population. Chronic care encompasses health promotion, prevention, self management, disease control, treatment and palliation to address 'chronicity' of long journeys through disease, illness and care in the varying contexts of complex health systems. Yet at an operational level, CCM activities are predominantly based on an evidence-base of discreet chronic disease interventions in specific settings; and their demonstrable impact is limited to processes of select disease management such as diabetes in specific disease management programs. This paper proposes a framework that makes sense of the nature of chronicity and its multiple dimensions beyond disease and argues for a set of building blocks and leverage points that should constitute the starting points for 'redesign'? Complex Adaptive Chronic Care is proposed as an idea for an explanatory and implementation framework for addressing chronicity in existing and future chronic care models. Chronicity is overtly conceptualized to encompass the phenomena of an individual journey, with simple and complicated, complex and chaotic phases, through long term asymptomatic disease to bodily dysfunction and illness, located in family and communities. Chronicity encompasses trajectories of self-care and health care, as health, illness and disease co-exist and co-evolve in the setting of primary care, local care networks and at times institutions. A systems approach to individuals in their multi-layered networks making sense of and optimizing experiences of their chronic illness would build on core values and agency around a local vision of health, empowerment of individuals and adaptive leadership, and it responds in line with the local values inherent in the community's disease-based knowledge and the local service's history and dynamics. Complex Adaptive Chronic Care exceeds the current notions of disease management as an endpoint. Primary care team members are system adaptors in partnership with individuals constructing their care and system leadership in response to chronic illness, and enable healthy resilience as well as personal healing and support. Outcomes of complex adaptive chronic care are the emergence of health in individuals and communities through adaptability, self-organization and empowerment. Chronic care reform from within a complex adaptive system framework is bottom up and emergent and stands in stark contrast to (but has to co-exist with) the prevailing protocol based disease care rewarding selective surrogate indicators of disease control. Frameworks such as the Chronic Care Model provide guidance, but do not replace individual experience, local adaptive leadership and responsiveness. The awareness of complexity means opening up problems to a different reality demanding different set of questions and approaches to answer them.


Anti-inflammatory properties of clovamide and Theobroma cacao phenolic extracts in human monocytes: evaluation of respiratory burst, cytokine release, NF-κB activation, and PPARγ modulation.
There is a great interest in the potential health benefits of biologically active phenolic compounds in cocoa (Theobroma cacao) and dark chocolate. We investigated the anti-inflammatory potential of clovamide (a N-phenylpropenoyl-L-amino acid amide present in cocoa beans) and two phenolic extracts from unroasted and roasted cocoa beans, by evaluating superoxide anion (O(2)(-)) production, cytokine release, and NF-κB activation in human monocytes stimulated by phorbol 12-myristate 13-acetate (PMA). The effects of rosmarinic acid are shown for comparison. Clovamide and rosmarinic acid inhibited PMA-induced O(2)(-) production and cytokine release (with a bell-shaped curve and maximal inhibition at 10-100 nM), as well as PMA-induced NF-κB activation; the two cocoa extracts were less effective. In all tests, clovamide was the most potent compound and also enhanced peroxisome proliferator-activated receptor-γ (PPARγ) activity, which may exert anti-inflammatory effects. These findings indicate clovamide as a possible bioactive compound with anti-inflammatory activity in human cells.


Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways.
The cytotoxic activity of ecteinascidin 743 (ET-743), a natural product derived from the marine tunicate Ecteinascidia turbinata that exhibits potent anti-tumor activity in pre-clinical systems and promising activity in phase I and II clinical trials, was investigated in a number of cell systems with well-defined deficiencies in DNA-repair mechanisms. ET-743 binds to N2 of guanine in the minor groove, but its activity does not appear to be related to DNA-topoisomerase I poisoning as the drug is equally active in wild-type yeast and in yeast with a deletion in the DNA-topoisomerase I gene. Defects in the mismatch repair pathway, usually associated with increased resistance to methylating agents and cisplatin, did not affect the cytotoxic activity of ET-743. However, ET-743 did show decreased activity (from 2- to 8-fold) in nucleotide excision repair (NER)-deficient cell lines compared to NER-proficient cell lines, from either hamsters or humans. Restoration of NER function sensitized cells to ET-743 treatment. The DNA double-strand-break repair pathway was also investigated using human glioblastoma cell lines MO59K and MO59J, respectively, proficient and deficient in DNA-dependent protein kinase (DNA-PK). ET-743 was more effective in cells lacking DNA-PK; moreover, pre-treatment of HCT-116 colon carcinoma cells with wortmannin, a potent inhibitor of DNA-PK, sensitized cells to ET-743. An increase in ET-743 sensitivity was also observed in ataxia telangiectasia-mutated cells. Our data strongly suggest that ET-743 has a unique mechanism of interaction with DNA.


Immunomodulatory and anti-cancer potential of cloves (Syzygium aromaticum) bud extract and its phytogenic silver nanoparticles.
Clove plant (Syzygium aromaticum) is one of the Myrtaceae family. It's a common flavor in food and the traditional medicine. The study's objective was to ascertain whether the clove bud aqueous extract (CAE) and CAE + nanosilver have any biological effects on immune cells and HT-29 colon cancer cell line. Nanosilver was produced through green synthesis approach using CAE. Produced nanosilver was characterized via electron microscope (scanning, SEM) and ultraviolet-visible spectroscopy. CAE and CAE + nanosilver were examined for their active biomolecules using FTIR analysis, p53 contents using real-time PCR, apoptosis and cell cycle arrest power on HT-29 cancer cell line via flow cytometerty and immunomodulatory potential utilizing MTT assay. Results cleared that a spherical nanosilver with a diameter range of 53 nm was formed by CAE. There were several active biomolecules in CAE and CAE + nanosilver. CAE and CAE + nanosilver increased the p53 protein expression and apoptotic cell number in HT-29 colon cancer cells. CAE and CAE + nanosilver could arrest HT-29 cells at the phase G2/M. CAE and CAE + nanosilver stimulated quiescent and PHA-pre-treated splenic cells at higher concentrations, and CAE suppressed quiescent splenic cell when diluted. In conclusion, the safe edible Syzygium aromaticum plant can be utilized to make anti-tumor agent, essentially for colon tumor. As Syzygium aromaticum plant could stimulate immune cells, it can be used as immune-stimulatory agent that can help fight tumor and tumor development.


(In)Congruence in Perceived Mother-child Cohesion and Informants' Depressive Symptoms: A Dyadic Response Surface Analysis.
Mother-child cohesion, reflecting the emotional connection between mothers and children, is a protective factor for individuals' mental health. The Modified Operations Triad Model suggests that children and mothers hold either congruent or incongruent views of their perceived cohesion, which reflects family functioning and is an indication of future mental health outcomes for family members. Despite increasing research on the impact of (in)congruence in perceived family functioning on children's mental health, few studies concurrently address the mental health of both mothers and children, overlooking their interdependence. This longitudinal study with multi-informant reports explored the long-term and developmental effects of (in)congruence in perceived mother-child cohesion on informants' depressive symptoms. A total of 577 families participated at the first time point, comprising 577 children (52.34% girls, Mage = 10.11 years) and 577 mothers (Mage = 37.32 years). The Dyadic Response Surface Analysis revealed that mother-child congruence at high levels of cohesion (versus low levels) predicted fewer depressive symptoms in mothers and children after three and nine months, as well as decreased depressive symptoms over nine months. Children who reported higher levels of cohesion than their mothers experienced fewer depressive symptoms after three months. Mothers with higher levels of cohesion than their children reported fewer depressive symptoms after three months. The current findings emphasize the importance of identifying and resolving discrepancies in perceived mother-child cohesion between mothers and children to promote a healthy family environment.